Zhu Et Al-2022-Cochrane Database of Systematic Reviews

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Cochrane Database of Systematic Reviews
Calcium channel blockers versus other classes of drugs for

hypertension (Review)
Zhu J, Chen N, Zhou M, Guo J, Zhu C, Zhou J, Ma M, He L
Zhu J, Chen N, Zhou M, Guo J, Zhu C, Zhou J, Ma M, He L.

Calcium channel blockers versus other classes of drugs for hypertension.
Cochrane Database of Systematic Reviews 2022, Issue 1. Art. No.: CD003654.
DOI: 10.1002/14651858.CD003654.pub6.
www.cochranelibrary.com
Calcium channel blockers versus other classes of drugs for hypertension (Review)
Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 3
BACKGROUND.............................................................................................................................................................................................. 9
OBJECTIVES.................................................................................................................................................................................................. 9
METHODS..................................................................................................................................................................................................... 9
RESULTS........................................................................................................................................................................................................ 11
Figure 1.................................................................................................................................................................................................. 12
Figure 2.................................................................................................................................................................................................. 15
Figure 3.................................................................................................................................................................................................. 16
Figure 4.................................................................................................................................................................................................. 18
Figure 5.................................................................................................................................................................................................. 20
Figure 6.................................................................................................................................................................................................. 22
DISCUSSION.................................................................................................................................................................................................. 23
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 25
ACKNOWLEDGEMENTS................................................................................................................................................................................ 25
REFERENCES................................................................................................................................................................................................ 26
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 33
DATA AND ANALYSES.................................................................................................................................................................................... 54
Analysis 1.1. Comparison 1: All-cause mortality, Outcome 1: CCBs vs other classes of antihypertensive agents........................... 55
Analysis 2.1. Comparison 2: Myocardial infarction, Outcome 1: CCBs vs other classes of antihypertensive agents....................... 57
Analysis 2.2. Comparison 2: Myocardial infarction, Outcome 2: Amlodipine vs ACE inhibitors....................................................... 58
Analysis 3.1. Comparison 3: Stroke, Outcome 1: CCBs vs other classes of antihypertensive agents............................................... 59
Analysis 3.2. Comparison 3: Stroke, Outcome 2: Amlodipine vs ARBs.............................................................................................. 60
Analysis 4.1. Comparison 4: Congestive heart failure, Outcome 1: CCBs vs other classes of antihypertensive agents................... 61
Analysis 5.1. Comparison 5: Cardiovascular mortality, Outcome 1: CCBs vs other classes of antihypertensive agents.................. 63
Analysis 5.2. Comparison 5: Cardiovascular mortality, Outcome 2: DHP vs β-blockers................................................................... 64
Analysis 6.1. Comparison 6: Major cardiovascular events, Outcome 1: CCBs vs other classes of antihypertensive agents............ 65
Analysis 6.2. Comparison 6: Major cardiovascular events, Outcome 2: Sensitivity analysis: CCBs vs ACE inhibitors...................... 66
Analysis 7.1. Comparison 7: Blood pressure reduction, Outcome 1: Systolic blood pressure reduction......................................... 67
Analysis 7.2. Comparison 7: Blood pressure reduction, Outcome 2: Diastolic blood pressure reduction....................................... 68
Analysis 7.3. Comparison 7: Blood pressure reduction, Outcome 3: Sensitivity analysis: CCBs vs ACE inhibitors.......................... 69
APPENDICES................................................................................................................................................................................................. 69
WHAT'S NEW................................................................................................................................................................................................. 77
HISTORY........................................................................................................................................................................................................ 77
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 78
DECLARATIONS OF INTEREST..................................................................................................................................................................... 78
SOURCES OF SUPPORT............................................................................................................................................................................... 78
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 78
NOTES........................................................................................................................................................................................................... 78
INDEX TERMS............................................................................................................................................................................................... 78
Calcium channel blockers versus other classes of drugs for hypertension (Review) i
Informed decisions.
[Intervention Review]
Calcium channel blockers versus other classes of drugs for hypertension
Jiaying Zhu1,2, Ning Chen1, Muke Zhou1, Jian Guo1, Cairong Zhu3, Jie Zhou1, Mengmeng Ma1, Li He1
1Department of Neurology, West China Hospital, Sichuan University, Chengdu, China. 2Department of Emergency, Gui Zhou Provincial
People's Hospital, Guiyang, China. 3Epidemic Disease & Health Statistics Department, School of Public Health, Sichuan University,
Chengdu, China
Contact: Li He, [email protected].
Editorial group: Cochrane Hypertension Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 1, 2022.
Citation: Zhu J, Chen N, Zhou M, Guo J, Zhu C, Zhou J, Ma M, He L. Calcium channel blockers versus other classes of drugs for
hypertension. Cochrane Database of Systematic Reviews 2022, Issue 1. Art. No.: CD003654. DOI: 10.1002/14651858.CD003654.pub6.
ABSTRACT
Background
This is the first update of a review published in 2010. While calcium channel blockers (CCBs) are often recommended as a first-line drug to
treat hypertension, the effect of CCBs on the prevention of cardiovascular events, as compared with other antihypertensive drug classes,
is still debated.
Objectives
To determine whether CCBs used as first-line therapy for hypertension are different from other classes of antihypertensive drugs in reducing
the incidence of major adverse cardiovascular events.
Search methods
For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled
trials (RCTs) up to 1 September 2020: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials
(CENTRAL 2020, Issue 1), Ovid MEDLINE, Ovid Embase, the World Health Organization International Clinical Trials Registry Platform, and
ClinicalTrials.gov. We also contacted the authors of relevant papers regarding further published and unpublished work and checked the
references of published studies to identify additional trials. The searches had no language restrictions.
Selection criteria
Randomised controlled trials comparing first-line CCBs with other antihypertensive classes, with at least 100 randomised hypertensive
participants and a follow-up of at least two years.
Data collection and analysis

Three review authors independently selected the included trials, evaluated the risk of bias, and entered the data for analysis. Any
disagreements were resolved through discussion. We contacted study authors for additional information.
Main results
This update contains five new trials. We included a total of 23 RCTs (18 dihydropyridines, 4 non-dihydropyridines, 1 not specified) with
153,849 participants with hypertension. All-cause mortality was not different between first-line CCBs and any other antihypertensive
classes. As compared to diuretics, CCBs probably increased major cardiovascular events (risk ratio (RR) 1.05, 95% confidence interval
(CI) 1.00 to 1.09, P = 0.03) and increased congestive heart failure events (RR 1.37, 95% CI 1.25 to 1.51, moderate-certainty evidence). As
compared to beta-blockers, CCBs reduced the following outcomes: major cardiovascular events (RR 0.84, 95% CI 0.77 to 0.92), stroke (RR
0.77, 95% CI 0.67 to 0.88, moderate-certainty evidence), and cardiovascular mortality (RR 0.90, 95% CI 0.81 to 0.99, low-certainty evidence).
As compared to angiotensin-converting enzyme (ACE) inhibitors, CCBs reduced stroke (RR 0.90, 95% CI 0.81 to 0.99, low-certainty evidence)
Calcium channel blockers versus other classes of drugs for hypertension (Review) 1
Informed decisions.
and increased congestive heart failure (RR 1.16, 95% CI 1.06 to 1.28, low-certainty evidence). As compared to angiotensin receptor blockers
(ARBs), CCBs reduced myocardial infarction (RR 0.82, 95% CI 0.72 to 0.94, moderate-certainty evidence) and increased congestive heart
failure (RR 1.20, 95% CI 1.06 to 1.36, low-certainty evidence).
Authors' conclusions
For the treatment of hypertension, there is moderate certainty evidence that diuretics reduce major cardiovascular events and congestive
heart failure more than CCBs. There is low to moderate certainty evidence that CCBs probably reduce major cardiovascular events more
than beta-blockers. There is low to moderate certainty evidence that CCBs reduced stroke when compared to angiotensin-converting
enzyme (ACE) inhibitors and reduced myocardial infarction when compared to angiotensin receptor blockers (ARBs), but increased
congestive heart failure when compared to ACE inhibitors and ARBs. Many of the differences found in the current review are not robust,
and further trials might change the conclusions. More well-designed RCTs studying the mortality and morbidity of individuals taking CCBs
as compared with other antihypertensive drug classes are needed for patients with different stages of hypertension, different ages, and
with different comorbidities such as diabetes.
PLAIN LANGUAGE SUMMARY
Calcium channel blockers versus other classes of drugs for hypertension
What is the aim of this review?
In this first update of a review published in 2010, we wanted to find out if calcium channel blockers (CCBs) can prevent harmful
cardiovascular events such as stroke, heart attack, and heart failure when compared to other antihypertensive (blood pressure-lowering)
medications used for individuals with raised blood pressure (hypertension).
Background
Appropriate lowering of elevated blood pressure in individuals with hypertension can reduce the amount of major complications of
hypertension, such as stroke, heart attack, congestive heart failure, and even death. CCBs are used as a first-line blood pressure-lowering
medication, but whether this is the best way to reduce harmful cardiovascular events has been a matter of debate.
Search date
We collected and analysed all relevant studies up to 01 September 2020.
Study characteristics
We found 23 relevant studies conducted in Europe, North America, Oceania, Israel, and Japan. The studies compared treatment with
CCBs versus treatment with other classes of blood pressure-lowering medications in people with hypertension and included 153,849
participants. Follow-up of trial participants ranged from 2 to 5.3 years.
Key results
There was no difference in deaths from all causes between CCBs and other blood pressure-lowering medications. Diuretics probably reduce
total cardiovascular events and congestive heart failure more than CCBs. CCBs probably reduce total cardiovascular events more than
beta-blockers. CCBs reduced stroke when compared to angiotensin-converting enzyme (ACE) inhibitors and reduced heart attack when
compared to angiotensin receptor blockers (ARBs), but increased congestive heart failure when compared to ACE inhibitors and ARBs.
Quality of the evidence
We assessed the quality of the evidence as mostly moderate, although more trials are desirable.
SUMMARY OF FINDINGS
Summary of findings 1. CCBs versus diuretic for hypertension
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CCBs versus diuretic for hypertension
Patient or population: patients with hypertension

Settings: outpatients or inpatients
Intervention: CCBs versus diuretic
Better health.
Informed decisions.
Trusted evidence.
Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of partici- Certainty of Comments
(95% CI) pants the evidence
Assumed risk Corresponding risk (studies) (GRADE)
Control CCBs versus diuretic
All-cause mortality Study population RR 0.98 35,057 ⊕⊕⊕⊝ NNH 83 (95%CI

Follow-up: 2 to 5 years (0.92 to 1.04) (5 studies) moderate1 53 to 187)
121 per 1000 118 per 1000
(111 to 126)
Myocardial infarction Study population RR 1.00 34,072 ⊕⊕⊕⊝ NNT 146 (95%CI
74 per 1000 74 per 1000
(68 to 79)
Stroke Study population RR 0.94 34,072 ⊕⊕⊕⊝ NNT 236 (95%CI

40 per 1000 37 per 1000
(33 to 42)

Congestive heart failure Study population RR 1.37 34,072 ⊕⊕⊕⊝ NNH 107 (95% CI
45 per 1000 62 per 1000
(56 to 68)
Cardiovascular mortality Study population RR 1.02 32,721 ⊕⊕⊕⊝ NNT 242 (95% CI
54 per 1000 55 per 1000
(50 to 60)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is
based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
3
CCB: calcium channel blocker; CI: confidence interval; RR: risk ratio; NNH: number needed to harm; NNT: number needed to treat
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GRADE Working Group grades of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: We are very uncertain about the estimate.
Better health.
Informed decisions.
Trusted evidence.
1All studies were blinded, but two of them did not describe the method of blinding. All studies mentioned randomisation, but only three studies provided details; only one study
described allocation concealment.
2All studies were blinded, but one of them did not describe the method of blinding. All studies mentioned randomisation, but two of them did not provide details; only one study
described allocation concealment.
3All four studies were blinded, but one of them did not describe the method of blinding. All studies mentioned randomisation, but two of them did not provide details; only one
study described allocation concealment.
Summary of findings 2. CCBs versus β-blocker for hypertension
CCBs versus β-blocker for hypertension

Intervention: CCBs versus β-blocker
Control CCBs versus β-blocker

All-cause mortality Study population RR 0.94 44,825 ⊕⊕⊕⊝ NNT 194 (95%CI
Follow-up: 2.7 to 5.5 years (0.88 to 1) (4 studies) moderate1 99 to 4004)
79 per 1000 74 per 1000
(70 to 79)
45 per 1000 41 per 1000
(36 to 46)
4
41 per 1000 32 per 1000
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(27 to 36)
Congestive heart failure Study population RR 0.83 19,915 ⊕⊕⊝⊝ NNT 279 (95%CI
Follow-up: 4 to 5 years (0.67 to 1.04) (2 studies) low2,3 141 to 12238)
18 per 1000 15 per 1000
(12 to 19)
Better health.
Informed decisions.
Trusted evidence.
Cardiovascular mortality Study population RR 0.90 44,825 ⊕⊕⊝⊝ NNT 279 (95%CI
Follow-up: 2.7 to 5.5 years (0.81 to 0.99) (4 studies) low1,4 145 to 3783)
35 per 1000 32 per 1000
(29 to 35)
CCB: calcium channel blocker; CI: confidence interval; RR: risk ratio; NNT: number needed to treat

1Only two studies described allocation concealment.

2Two studies did not describe allocation concealment.
3Wide 95% CI crossing the line of no effect and low event rate.
4I2 > 60%. Effect size varied considerably.

Summary of findings 3. CCBs versus ACE inhibitor for hypertension
CCBs versus ACE inhibitor for hypertension

Intervention: CCBs versus ACE inhibitor
5
Control CCBs versus ACE inhibitor
All-cause mortality Study population RR 0.97 27,999 ⊕⊕⊝⊝ NNT 282 (95%CI
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Follow-up: 3 to 5 years (0.91 to 1.03) (7 studies) low1,2 89 to 240)
126 per 1000 122 per 1000
(115 to 130)
Myocardial infarction Study population RR 1.05 27,999 ⊕⊕⊝⊝ NNT 235 (95%CI
Follow-up: 3 to 5.3 years (0.97 to 1.14) (7 studies) low1,3 96 to 541)
Better health.
Informed decisions.
Trusted evidence.
71 per 1000 75 per 1000
(69 to 81)
Stroke Study population RR 0.90 27,999 ⊕⊕⊝⊝ NNT 185 (95%CI

Follow-up: 3 to 5.3 years (0.81 to 0.99) (7 studies) low1,2 95 to 2863)
52 per 1000 47 per 1000
(42 to 51)
Congestive heart failure Study population RR 1.16 25,276 ⊕⊕⊝⊝ NNT 94 (95%CI 59
Follow-up: median 3 years (1.06 to 1.28) (5 studies) low4,5 to 222)
63 per 1000 73 per 1000
(66 to 80)
Cardiovascular mortality Study population RR 0.98 27,619 ⊕⊕⊕⊝ NNT 923 (95%CI
62 per 1000 61 per 1000
(55 to 66)
ACE: angiotensin-converting enzyme; CCB: calcium channel blocker; CI: confidence interval; RR: risk ratio; NNT: number needed to treat

1In one study, study drugs were administered open-label. All studies mentioned randomisation, but two of them did not provide details; only three studies described allocation
concealment.
2In one study, when BP was not well-controlled on monotherapy, the other study drug was added.
3I2 > 60%; direction and size of effect inconsistent.
4All studies mentioned randomisation, but two of them did not provide details; only two studies described allocation concealment.
5Wide 95% CI crossing the line of no effect and low event rate.
6
6All studies mentioned randomisation, but two of them did not provide details; only three studies described allocation concealment.
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Summary of findings 4. CCBs versus ARB for hypertension
CCBs versus ARB for hypertension

Intervention: CCBs versus ARB
Better health.
Informed decisions.
Trusted evidence.
Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of partici- Certainty of comments
Control CCBs versus ARB
All-cause mortality Study population RR 1.00 25,611 ⊕⊕⊕⊝ NNT 3128 (95%CI
Follow-up: 2 to 5.5 years (0.92 to 1.08) (6 studies) moderate1 143 to 157)
81 per 1000 81 per 1000
(75 to 88)
Follow-up: 2 to 5.5 years (0.72 to 0.94) (6 studies) moderate1 93 to 492)
36 per 1000 29 per 1000
(26 to 34)

Follow-up: 2.6 to 5.5 (0.76 to 1.00) (6 studies) moderate2 115 to 8570)
34 per 1000 30 per 1000
(26 to 34)
Congestive heart failure Study population RR 1.20 23,265 ⊕⊕⊝⊝ NNT 94 (95%CI 59

Follow-up: mean 2.6 years (1.06 to 1.36) (5 studies) low1,3 to 222)
38 per 1000 45 per 1000
(40 to 51)
Cardiovascular mortality Study population RR 0.79 4642 ⊕⊕⊕⊝ NNT 184 (95% CI
Follow-up: mean 2 years (0.54 to 1.15) (3 studies) moderate4 72 to 331)
25 per 1000 20 per 1000
(13 to 29)
7
ARB: angiotensin receptor blocker; CCB: calcium channel blocker; CI: confidence interval; RR: risk ratio; NNT: number needed to treat
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1Only two studies described allocation concealment, and one study had withdrawals.
Better health.
Informed decisions.
Trusted evidence.
2Only three studies described allocation concealment, and one study had withdrawals.
3I2 > 60%; direction and size of effect inconsistent.
4One study of three did not describe allocation concealment, and one study had withdrawals.

8
Informed decisions.
BACKGROUND METHODS
Description of the condition Criteria for considering studies for this review
Hypertension is a leading cause of death worldwide, and its Types of studies
prevalence has increased dramatically over the past two decades
We included randomised controlled trials (RCTs) that randomised
(GBD 2015). In the population-based ARIC (Atherosclerosis Risk
100 or more participants and followed participants for at least two
in Communities) study, hypertension was associated with an
years.
increased risk of coronary heart disease, stroke, heart failure, and
end-stage renal disease; 25% of all cardiovascular events were Types of participants
attributable to hypertension (Cheng 2014).
We included participants with a baseline blood pressure (BP) of
Description of the intervention at least 140 mmHg systolic or 90 mmHg diastolic, measured in
a standard way on at least two occasions, or participants with
Antihypertensive therapies have established benefits in reducing diabetes mellitus with a BP of more than 135/85 mmHg. If a trial
the risk for major cardiovascular events. Pharmacotherapy for was not limited to participants with elevated BP, it must have
high blood pressure includes first-line agents, such as diuretics, reported outcome data separately for participants with elevated BP
angiotensin-converting enzyme (ACE) inhibitors, angiotensin as defined above.
receptor blockers (ARBs), and calcium channel blockers (CCBs),
and non-first-line agents, such as beta-blockers and alpha-blockers Types of interventions
(Whelton 2018).
We included trials comparing first-line CCBs with other first-line
How the intervention might work antihypertensive classes. The majority (> 70%) of participants in
all study groups must be taking the assigned drug class after one
Different classes of antihypertensive drugs have different year. Supplemental drugs from drug classes other than CCBs were
mechanisms of action. Previous meta-analysis demonstrated that allowed as stepped therapy.
all major antihypertensive drug classes (diuretics, ACE inhibitors,
ARBs, beta-blockers, and CCBs) caused a similar reduction in Types of outcome measures
coronary heart disease events and stroke for a given reduction in
blood pressure (Law 2009). The systematic review for the 2017 ACC/ The main outcomes of the review were as follows.
AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline Primary outcomes
for the prevention, detection, evaluation, and management of
high blood pressure in adults indicated that thiazides were 1. All-cause mortality
associated with a lower risk of many cardiovascular outcomes 2. Myocardial infarction (non-fatal and fatal MI plus sudden or
compared with other antihypertensive drug classes (Reboussin rapid death)
2017). CCBs significantly increased the risk of congestive heart 3. Stroke (non-fatal and fatal stroke)
failure as compared to diuretics, ACE inhibitors, and ARBs in a
4. Congestive heart failure
review by Thomopoulos(Thomopoulos 2015). One previous review
concluded that beta-blockers reduced total cardiovascular events 5. Cardiovascular mortality
significantly less than CCBs (Wiysonge 2007). 6. Major cardiovascular events (MI, congestive heart failure, stroke,
and cardiovascular mortality)
Why it is important to do this review
Secondary outcomes
The issue of first-line drug selection is highly relevant for millions
of subjects receiving drug therapy for hypertension. The benefits 1. Reduction in systolic and diastolic blood pressure
in reducing the risk for major cardiovascular events of any one
class of antihypertensive therapies relative to other classes has Search methods for identification of studies
been a matter of debate. Our first systematic review compared Electronic searches
CCBs with other classes of antihypertensive drugs in 2010 (Chen
2010), but since then some head-to-head trials of CCBs versus other For this update, the Cochrane Hypertension Information Specialist
classes of antihypertensive drugs have been performed. These searched the following databases without language or publication
additional newer trials not included in previous systematic reviews status restrictions:
may provide an improved understanding of the relative benefits of
• the Cochrane Hypertension Specialised Register via the
each class of antihypertensive therapies. This review update aims
Cochrane Register of Studies (CRS-Web) (searched 01
to sent the outcome data in a way that best assists clinicians in the
September 2020);
choice of a antihypertensive drug.
• the Cochrane Central Register of Controlled Trials (CENTRAL,
OBJECTIVES 2020, Issue 1) via CRS-Web (searched 01 September 2020);
• MEDLINE Ovid, MEDLINE Ovid Epub Ahead of Print, and MEDLINE
To determine whether CCBs used as first-line therapy for Ovid In-Process & Other Non-Indexed Citations (searched 01
hypertension are different from other classes of antihypertensive September 2020);
drugs in reducing the incidence of major adverse cardiovascular • Embase Ovid (searched 01 September 2020);
events.
Informed decisions.
• US National Institutes of Health Ongoing Trials Measures of treatment effect

Register ClinicalTrials.gov (www.clinicaltrials.gov) (searched 01
We based quantitative analysis of outcomes on intention-to-treat
September 2020);
principles as much as possible. For dichotomous outcomes, we
• World Health Organization International Clinical Trials Registry expressed results as the risk ratio (RR) with a 95% confidence
Platform (www.who.it.trialsearch) (searched 01 September interval (CI). For combining continuous variables (systolic blood
2020). pressure reduction, diastolic blood pressure reduction), we used
the mean difference (with 95% CI).
The Information Specialist modelled subject strategies for
databases on the search strategy designed for MEDLINE. Unit of analysis issues
Where appropriate, these were combined with subject strategy
adaptations of the Highly Sensitive Search Strategy designed by The unit of analysis was the individual trial. For trials having more
Cochrane for identifying randomised controlled trials (as described than two arms, we only included arms relevant to this review. For
in the Cochrane Handbook for Systematic Reviews of Interventions trials included more than one intervention group with a single
Version 5.1.0, Box 6.4.c.)(Higgins 2011). The database search comparator arm, we included both intervention groups.
strategies are shown for this update in Appendix 1 and from the
previous (2010) review in Appendix 2. Dealing with missing data
We contacted study investigators in the case of missing data. We
Searching other resources based the quantitative analyses of outcomes on intention-to-treat
• The Cochrane Hypertension Information Specialist searched results.
the Hypertension Specialised Register segment (which includes
searches of MEDLINE, Embase, and Epistemonikos for Assessment of heterogeneity
systematic reviews) to retrieve existing reviews relevant to this We used Chi2 and I2statistics to test for heterogeneity of treatment
systematic review, so that we could scan their reference lists for effect among trials.
additional trials. The Specialised Register also includes searches
of CAB Abstracts & Global Health, CINAHL (Cumulative Index to We assessed values of the I2statistic as follows (Higgins 2011a):
Nursing and Allied Health Literature), ProQuest Dissertations &
Theses, and Web of Science for controlled trials. • 0% to 40%: heterogeneity might not be important;
• We checked the bibliographies of included studies and any • 30% to 60%: moderate heterogeneity;
relevant systematic reviews identified for further references to • 50% to 90%: substantial heterogeneity;
relevant trials. • 75% to 100% considerable heterogeneity.
• Where necessary, we contacted authors of key papers and
abstracts to request additional information about their trials. We used the fixed-effect model when there was homogeneity and
used the random-effects model to test for statistical significance
Data collection and analysis where there was heterogeneity.
Selection of studies Assessment of reporting biases
Two review authors (Jiaying Zhu, Ning Chen) independently We planned to assess reporting bias following the
examined the titles and abstracts of citations identified by recommendations on testing for funnel plot asymmetry as
the electronic searches for possible inclusion. We retrieved described in the Cochrane Handbook for Systematic Reviews of
full-text publications of potentially relevant studies and three Interventions (Higgins 2011a).
review authors (Jiaying Zhu, Jie Zhou and Mengmeng Ma)
then independently determined study eligibility. We resolved Data synthesis
disagreements about study eligibility by discussion and, if
We performed data synthesis and analyses using the Cochrane
necessary, a fourth review author would arbitrate.
Review Manager software, RevMan 5.4, We describe data results in
Data extraction and management tables and forest plots. We also give full details of all studies we
include and exclude. We have included a standard PRISMA flow
Three review authors (Jiaying Zhu, Jie Zhou and Mengmeng Ma) diagram.
independently extracted data using a standard form, and then
cross-checked them. Muke Zhou and Jian Guo confirmed all Subgroup analysis and investigation of heterogeneity
numeric calculations and graphic interpolations. We resolved any
If appropriate, we would perform subgroup analyses.
discrepancies by consensus.
Heterogeneity among participants could be related to: age,gender,
Assessment of risk of bias in included studies
baseline blood pressure, target blood pressure, high-risk
The review authors (Jiaying Zhu and Mengmeng Ma) independently participants, participants with comorbid conditions.
used the Cochrane 'Risk of bias' tool to categorize studies as Heterogeneity in treatments could be related to: form of
having low,unclear, or high risk of bias for sequence generation, drugs,dosage of drugs, or duration of therapy.
allocation sequence concealment, loss of blinding, selective
reporting,incomplete reporting of outcomes, and other potential Sensitivity analysis
sources of bias (Higgins 2011a). We planned to conduct sensitivity analyses to examine the effects
of excluding studies with a moderate or high risk of bias, as
Informed decisions.
described in the Cochrane Handbook for Systematic Reviews of for Systematic Reviews of Interventions (Schünemann 2011a;
Interventions (Higgins 2011) Schünemann 2011b). We justified all decisions to downgrade the
quality of the evidence using footnotes and made comments to aid
reader's understanding of the review where necessary.
Summary of findings and assessment of the certainty of the
evidence RESULTS
In this updated review, we included 'Summary of findings' tables
Description of studies
for comparisons that included more than one trial to present the
main findings of the review, which included information about the See Characteristics of included studies; Characteristics of excluded
quality of the evidence, the magnitude of effects, and the sum of studies.
the available data on the main outcomes (Schünemann 2011a).
Results of the search
We assessed the quality of a body of evidence according to five
The results of the search are shown in the PRISMA diagram (Figure
GRADE considerations (study limitations, inconsistency of effect,
1), We identified 4,700 records from database searches. 4,649
imprecision, indirectness, and publication bias) (Ryan 2016). We
records remained after removal of duplicates. After screening titles
downgraded the evidence from 'high certainty by one level where
and abstracts, we obtained 65 full-text articles. Of these articles,
one of these factors was present to a serious degree and two
we excluded 42 studies based on them not meeting our inclusion
levels if very serious. We used the methods and recommendations
criteria.
described in Chapter 8 and Chapter 12 of the Cochrane Handbook
Informed decisions.
Figure 1. Study flow diagram.
Informed decisions.
Figure 1. (Continued)
Included studies BP ≥ 90 mmHg) separately, so data for hypertensive participants

could be extracted.
See Characteristics of included studies for details.
Additional inclusion criteria varied for each study, as follows: with
We included 23 RCTs (AASK; ABCD; ALLHAT; ASCOT-BPLA; CASE-
other risk factor(s) for coronary heart disease or cardiovascular
J; CONVINCE; ELSA; FACET; HOMED-BP; IDNT; INSIGHT; INVEST;
disease (ALLHAT; ASCOT-BPLA; CASE-J; CONVINCE; INSIGHT); with
J-MIC(B); MIDAS; NAGOYA; NICS-EH; NORDIL; SHELL; STOP-
coronary heart disease (INVEST; J-MIC(B)); with cardiovascular risk
Hypertension-2; TOMHS; VALUE; VART; VHAS) with a total of 153,849
factors or cardiovascular disease (VALUE); with type 2 diabetes
participants. Five of the 23 trials were new in this update (CASE-J;
mellitus (non-insulin-dependent diabetes mellitus), ABCD; FACET,
HOMED-BP; J-MIC(B); NAGOYA; VART).
or type 2 diabetes mellitus and nephropathy (IDNT); with glucose
All the included RCTs supplied explicit inclusion and exclusion intolerance (type 2 diabetes or impaired glucose tolerance)
criteria. Twenty trials included only hypertensive participants, (NAGOYA); African-Americans with hypertensive kidney disease
but these were defined differently, as follows: 140/90 mmHg or (AASK).
more (FACET; INVEST; NAGOYA; VART); 150/90 mmHg or more (J-
MIC(B)); more than 160/95 mmHg (VHAS); more than 135/85 mmHg
All 23 included RCTs recruited participants of both sexes, but age
for participants with diabetes mellitus (IDNT); 140 to 179 mmHg
requirements differed amongst the trials, as follows: ≥ 30 years
systolic and/or 90 to 109 mmHg diastolic (ALLHAT); 150 to 210
(VART); > 40 years (HOMED-BP; MIDAS); > 50 years (INVEST; VALUE);
mmHg systolic and 95 to 115 mmHg diastolic (ELSA); systolic BP ≥
> 55 years (ALLHAT; CONVINCE); > 60 years (NICS-EH; SHELL); 18 to
180 mmHg and/or diastolic BP ≥ 105 mmHg (STOP-Hypertension-2);
70 years (AASK); 30 to 70 years (IDNT); 30 to 75 years (NAGOYA); 40
diastolic BP of 100 mmHg or more, NORDIL, or of 90 to 99 mmHg
to 65 years (VHAS); 40 to 74 years (ABCD); 40 to 79 years (ASCOT-
(TOMHS); treated hypertension with an upper limit of 175/100
BPLA); 45 to 69 years (TOMHS); 45 to 75 years (ELSA); 50 to 74 years
mmHg or untreated hypertension of 140 to 190 mmHg systolic or
(NORDIL); 55 to 80 years (INSIGHT); under 75 years (J-MIC(B)); 70
90 to 110 mmHg diastolic (CONVINCE); BP ≥ 160/100 mmHg for
to 84 years (STOP-Hypertension-2). In the CASE-J trial, differing BP
participants with untreated hypertension or BP ≥ 140/90 mmHg for
levels were required for participants aged < 70 years and ≥ 70 years.
participants on antihypertensive treatment (ASCOT-BPLA); systolic
BP ≥ 150 mmHg and diastolic BP ≥ 95 mmHg, or only systolic BP Most trials followed a goal BP in their protocols, mostly less than
≥ 160 mmHg (INSIGHT); only diastolic BP ≥ 95 mmHg, AASK, or 90 140/90 mmHg (ALLHAT; ASCOT-BPLA; CONVINCE; FACET; INSIGHT;
to 115 mmHg (MIDAS); 160 to 210/220 mmHg systolic and less than INVEST; VALUE; VART); or less than 150/90 mmHg (J-MIC(B)); less
115 mmHg diastolic (NICS-EH; VALUE); ≥ 160 mmHg systolic and ≤ than 130/80 mmHg for hypertensive participants with glucose
95 mmHg diastolic (SHELL); systolic BP ≥ 140 mmHg or diastolic BP intolerance (NAGOYA); less than 130/85 mmHg for participants
≥ 90 mmHg in participants < 70 years old, or systolic BP ≥ 160 mmHg with diabetes or renal impairment (ASCOT-BPLA; INVEST); ≤ 135/85
or diastolic BP ≥ 90 mmHg in participants ≥ 70 years old (CASE-J); mmHg or a decrease ≥ 10 mmHg systolic for diabetic participants
mild-to-moderate hypertension (HOMED-BP). Only one trial did not (IDNT); ≤ 160/95 mmHg (STOP-Hypertension-2); less than 90 mmHg
limit participants to elevated BP (diastolic BP ≥ 80 mmHg) (ABCD), diastolic, NORDIL, or 95 mmHg (TOMHS); less than 95 mmHg with
but it reported outcomes on participants with elevated BP (diastolic a fall of at least 5 mmHg (ELSA); less than 90 mmHg with a fall
Informed decisions.
of at least 10 mmHg (MIDAS); reduction more than 20 mmHg or Review Manager 5 for analysis. In some other trials, mean BP
systolic BP ≤ 160 mmHg (SHELL); ≤ 90 mmHg or ≤ 95 mmHg with change could be calculated by subtracting the baseline value at
a reduction of at least 10% from baseline value (VHAS); 75 mmHg randomisation from the value reported at the end of the trial,
or less diastolic in the intensive-treatment group and 80 to 89 but SDs for changes were not reported. We calculated change-
mmHg diastolic in the moderate-treatment group (ABCD); 102 to from-baseline SDs when baseline and final values were known
107 mmHg of mean arterial pressure in the usual-goal group and (Higgins 2011b) (AASK; ALLHAT; FACET; NICS-EH; NORDIL; VALUE).
92 mmHg or less in the lower-goal group (AASK); a decrease ≥ 20 However, when trials did not supply SDs for the baseline and
mmHg of BP if systolic BP was more than 160 mmHg or diastolic final BPs, the BP results were not entered into the meta-analysis
BP was more than 110 mmHg (FACET); 60 years old, systolic BP/ (ABCD; ASCOT-BPLA; CASE-J; CONVINCE; ELSA; HOMED-BP; IDNT;
diastolic BP 130/85 mmHg; 60 to 69 years old, systolic BP/diastolic INSIGHT; J-MIC(B); MIDAS; NAGOYA; SHELL; STOP-Hypertension-2;
BP 140/90 mmHg; 70 to 79 years old, systolic BP/diastolic BP 150/90 VART; VHAS).
mmHg; 80 years old, systolic BP/diastolic BP 160/90 mmHg (CASE-
J); usual control 125 to 134/80 to 84 mmHg and tight control < 125/ Mean duration of follow-up ranged from 2 to 5.3 years. One trial
< 80 mmHg (HOMED-BP). stated that no participant was lost to follow-up and no participant
refused to continue in the study (STOP-Hypertension-2), whilst loss
Of CCBs for hypertension, dihydropyridines (DHPs) were the most to follow-up and withdrawal were reported in the other 22 trials.
commonly studied, especially amlodipine (AASK; ALLHAT; ASCOT- All trials with the exception of NICS-EH stated that an intention-to-
BPLA; CASE-J; FACET; IDNT; NAGOYA; TOMHS; VALUE; VART). treat analysis was performed.
Other DHPs studied included nifedipine (INSIGHT; J-MIC(B)),
felodipine (STOP-Hypertension-2), nisoldipine (ABCD), nicardipine Excluded studies
(NICS-EH), lacidipine (ELSA; SHELL), and isradipine (MIDAS). Other See Characteristics of excluded studies for details.
trials evaluated non-DHPs such as an aralkylamine derivative
verapamil, CONVINCE; INVEST; VHAS, and a benzothiazepine The reasons for exclusion included: non-randomised design
derivative diltiazem (NORDIL). One study did not describe the (Abascal 1998; Bhad 2011; DHCCP; Pahor 1995; Psaty 1995);
specific CCBs used (HOMED-BP). The included RCTs compared the control group used placebo instead of other classes of
one of the above CCBs to other classes of antihypertensive antihypertensive drugs (Chen 2013; STONE; Syst-China; Syst-
drugs, including: a diuretic (ALLHAT; INSIGHT; MIDAS; NICS-EH; Eur); the comparison was performed between different kinds
SHELL; TOMHS; VHAS); a beta-blocker (AASK; ASCOT-BPLA; ELSA; of CCBs, without any other classes of antihypertensive drugs
INVEST; TOMHS); a diuretic or beta-blocker, or both, data of (Abe 2013; Kes 2003); the follow-up was shorter than two years
which could not be separated for each drug (CONVINCE; NORDIL; (Espinel 1992; GLANT; Gottdiener 1997; Kereiakes 2012; Leon 1993;
STOP-Hypertension-2); an alpha-1-antagonist (TOMHS); an ACE Papademetriou 1997; PRESERVE; Schneider 1991; Van Leeuwen
inhibitor (AASK; ABCD; ALLHAT; FACET; HOMED-BP; J-MIC(B); STOP- 1995; Weir 1990; Zhang 2012); small sample of participants (fewer
Hypertension-2; TOMHS); or an ARB (CASE-J; HOMED-BP; IDNT; than 100 were randomised) (Bakris 1996; Bakris 1997; FACTS; Kim
NAGOYA; VALUE; VART). 2011; Maharaj 1992; Mesci 2011; Radevski 1999); cannot make a
separate comparison of CCB with other classes antihypertensive
Supplemental antihypertensive agents other than the study drugs because of combination drug use (ACCOMPLISH; BEAHIT;
drugs were permitted in most of the included trials, often Calhoun 2013; Cicero 2012; COLM; DEMAND; FEVER; Kojima 2013;
administered sequentially to achieve BP goals (AASK; ABCD; Lauria 2012; OSCAR; Wen 2011); study groups differed in target BPs
ALLHAT; ASCOT-BPLA; CASE-J; CONVINCE; ELSA; HOMED-BP; IDNT; instead of drug classes (HOT); to avoid repeated inclusion of the
INSIGHT; INVEST; J-MIC(B); MIDAS; NAGOYA; NORDIL; SHELL; STOP- research population in extended trial (CASE-J Ex).
Hypertension-2; VALUE; VART; VHAS). The FACET trial added the
study drug of the other group to participants whose BP was not Risk of bias in included studies
controlled well. The TOMHS trial studied five classes of first-line
antihypertensive drugs, and added chlortalidone or enalapril, both Since trials with a small sample were excluded from the current
of which were study drugs, to participants to control BP. NICS- review, most of included trials were large and multicentre with
EH prohibited the use of any other antihypertensive drugs. standardised protocols. We evaluated the methodological quality
of the included trials in several ways. According to the summary
Outcomes differed amongst studies, but results for our planned assessment of the risk of bias for each important outcome (Higgins
outcomes of cardiovascular events and BP changes were reported 2011a), we assessed five trials as at low risk of bias (ALLHAT; ASCOT-
in most trials. However, fatal MI, stroke, and heart failure BPLA CASE-J; IDNT; INVEST; J-MIC(B)), two trials as at high risk of
were sometimes contained in death events, and in some trials bias (FACET; NICS-EH), and the remaining 16 trials as at unclear
components of cardiovascular events were not reported separately. risk of bias. The risk of bias graph (Figure 2) shows judgements of
As a result, not every trial supplied data to each meta-analysis the review authors about each domain presented as percentages
for outcomes of this review. Only two trials explicitly presented across all included studies. The risk of bias summary (Figure 3)
the mean BP changes with standard deviations (SDs), INVEST, or shows review authors' judgements about each risk of bias item for
standard errors, TOMHS, which could be directly inputted into each included study.
Informed decisions.
Figure 2. Methodological quality graph: review authors' judgements about each methodological quality item
presented as percentages across all included studies.
Random sequence generation (selection bias)

Allocation concealment (selection bias)
Blinding (performance bias and detection bias): All outcomes
Incomplete outcome data (attrition bias): All outcomes
Selective reporting (reporting bias)
Other bias
0% 25% 50% 75% 100%
Low risk of bias Unclear risk of bias High risk of bias
Informed decisions.
Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Blinding (performance bias and detection bias): All outcomes

Incomplete outcome data (attrition bias): All outcomes
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Selective reporting (reporting bias)

AASK Other bias
+ ? + + + +
ABCD ? ? + + + +
ALLHAT + + + + + +
ASCOT-BPLA + + + + + +
CASE-J + + + + + +
CONVINCE + + + + + ?
ELSA + ? + + + +
FACET + ? - + + -
HOMED-BP + ? + + + +
IDNT + + + + + +
INSIGHT ? ? + ? + +
INVEST + - + + + +
J-MIC(B) + + + + + +
MIDAS + ? + + + +
NAGOYA + ? + + + ?
NICS-EH ? ? + - + +
NORDIL ? + + + + ?
SHELL + ? ? + + +
STOP-Hypertension-2 ? ? + + + +
TOMHS + ? + + + +
VALUE + ? + ? + +
VART + ? + + + +
VHAS ? ? ? + + +
Informed decisions.
Allocation misconduct (ALLHAT; ASCOT-BPLA; CONVINCE; INSIGHT), which

could have led to attrition bias.
All of the included studies were stated as randomised controlled
trials. A computer-generated code for randomisation was Selective reporting
often used, but eight trials did not report the methods of
allocation (ABCD; HOMED-BP; INSIGHT; NICS-EH; NORDIL; STOP- In this review, we judged all included studies to have a low risk of
Hypertension-2; VART; VHAS). Allocation concealment was seldom reporting bias.
described; only four trials stated that their randomisation codes
Other potential sources of bias
were concealed at the clinical trials centre (ALLHAT; ASCOT-BPLA;
IDNT; INVEST), whilst in the CONVINCE trial, an interactive voice In FACET trial, when BP was not controlled well on monotherapy,
response system for randomising, assigning, and tracking blinded the other study drug was added. In NORDIL trial, a diuretic or
medication was used. Information was insufficient to assess this blocker was added in step 3, and any other antihypertensive
'Risk of bias' domain for the remaining trials. compound could be added as step 4 in the diltiazem group. This
could have affected the evaluation of effect of each study drug.
Blinding
All the included trials compared two first-line antihypertensive drug Effects of interventions
classes to each other. With exception of the FACET trial, which See: Summary of findings 1 CCBs versus diuretic for hypertension;
was open-label, the included studies were stated as blinded. In Summary of findings 2 CCBs versus β-blocker for hypertension;
some trials active drugs were described as of indistinguishable Summary of findings 3 CCBs versus ACE inhibitor for hypertension;
appearance, but it was still impossible to know the extent Summary of findings 4 CCBs versus ARB for hypertension
of blinding (Higgins 2011a). Nine trials used a Prospective,
Randomised, Open-label, Blinded Endpoint (PROBE) design The diuretic and beta-blocker subgroup included data from three
(ASCOT-BPLA; CASE-J; HOMED-BP; INVEST; J-MIC(B); NAGOYA; studies in which a diuretic, a beta-blocker, or both were used but
NORDIL; STOP-Hypertension-2; VART), which differs from the could not be separately analysed.
classical double-blind method. In a PROBE study, outcomes are
evaluated by a blinded endpoint committee to avoid detection All-cause mortality
bias; in this way treatment allocation might be open to risk of The effect of CCBs on death from any cause was not significantly
performance bias from participants and doctors (Hansson 1992). different from that of any other evaluated agents: diuretics (5
trials with 35,057 participants: risk ratio (RR) 0.98, 95% confidence
Incomplete outcome data
interval (CI) 0.92 to 1.04, I2 = 0%; moderate-certainty evidence);
Missing data caused by loss to follow-up or withdrawals were on beta-blockers (4 trials with 44,825 participants: RR 0.94, 95% CI 0.88
the whole equal amongst the treatment groups, and an intention- to 1.00, P = 0.54, I2 = 0%; moderate-certainty evidence); diuretics
to-treat analysis, which meant data were analysed according to and beta-blockers (3 trials with 31,892 participants: RR 1.03, 95% CI
randomised treatment assignments regardless of the subsequent 0.94 to 1.12, I2 = 0%; moderate-certainty evidence); ACE inhibitors (7
medications (Fergusson 2002), was performed in most of the trials with 27,999 participants: RR 0.97, 95% CI 0.91 to 1.03, I2 = 0%;
included trials, with the exception of the STOP-Hypertension-2 trial low-certainty evidence); and ARBs (6 trials with 25,611 participants:
(with negligible loss) and the NICS-EH trial. Some sites and their
RR 1.00, 95% CI 0.92 to 1.08, I2 = 0%; moderate-certainty evidence)
participants were excluded after randomisation because of poor
(Analysis 1.1; Figure 4).
documentation of informed consent, data integrity concerns, or
Informed decisions.
Figure 4. Forest plot of comparison: 1 All-cause mortality, outcome: 1.1 CCBs versus other classes of
antihypertensive agents.
CCBs Other agents Risk Ratio Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI
1.1.1 CCBs vs diuretics

ALLHAT 1256 9048 2203 15255 85.1% 0.96 [0.90 , 1.03]
INSIGHT 153 3289 152 3286 7.9% 1.01 [0.81 , 1.25]
MIDAS 8 442 9 441 0.5% 0.89 [0.35 , 2.28]
SHELL 145 942 122 940 6.3% 1.19 [0.95 , 1.48]
VHAS 5 707 4 707 0.2% 1.25 [0.34 , 4.64]
Subtotal (95% CI) 14428 20629 100.0% 0.98 [0.92 , 1.04]
Total events: 1567 2490
Heterogeneity: Chi² = 3.38, df = 4 (P = 0.50); I² = 0%
Test for overall effect: Z = 0.69 (P = 0.49)
1.1.2 CCBs vs β-blockers

AASK 22 217 49 441 1.8% 0.91 [0.57 , 1.47]
ASCOT-BPLA 738 9639 820 9618 46.6% 0.90 [0.82 , 0.99]
ELSA 13 1177 17 1157 1.0% 0.75 [0.37 , 1.54]
INVEST 873 11267 893 11309 50.6% 0.98 [0.90 , 1.07]
Subtotal (95% CI) 22300 22525 100.0% 0.94 [0.88 , 1.00]
1.1.3 CCBs vs diuretics or β-blockers

CONVINCE 337 8241 319 8361 34.8% 1.07 [0.92 , 1.25]
NORDIL 231 5410 228 5471 24.9% 1.02 [0.86 , 1.23]
STOP-Hypertension-2 362 2196 369 2213 40.3% 0.99 [0.87 , 1.13]
Subtotal (95% CI) 15847 16045 100.0% 1.03 [0.94 , 1.12]
1.1.4 CCBs vs ACE inhibitors

AASK 22 217 34 436 1.3% 1.30 [0.78 , 2.17]
ABCD 18 235 14 235 0.8% 1.29 [0.65 , 2.52]
ALLHAT 1256 9048 1314 9054 74.4% 0.96 [0.89 , 1.03]
FACET 5 191 4 189 0.2% 1.24 [0.34 , 4.54]
HOMED-BP 25 1171 17 1172 1.0% 1.47 [0.80 , 2.71]
J-MIC(B) 12 828 15 822 0.9% 0.79 [0.37 , 1.69]
Subtotal (95% CI) 13886 14113 100.0% 0.97 [0.91 , 1.03]
1.1.5 CCBs vs ARBs

CASE-J 86 2349 73 2354 7.0% 1.18 [0.87 , 1.60]
HOMED-BP 25 1171 16 1175 1.5% 1.57 [0.84 , 2.92]
IDNT 83 567 87 579 8.3% 0.97 [0.74 , 1.29]
NAGOYA 16 575 22 575 2.1% 0.73 [0.39 , 1.37]
VALUE 818 7596 841 7649 80.8% 0.98 [0.89 , 1.07]
VART 3 511 2 510 0.2% 1.50 [0.25 , 8.92]
Subtotal (95% CI) 12769 12842 100.0% 1.00 [0.92 , 1.08]
Informed decisions.
0.5 0.7 1 1.5 2

Favours CCBs Favours other agents
MI (non-fatal and fatal MI plus sudden or rapid death) of seven trials involving ACE inhibitors studied DHPs, but three of
them gave participants amlodipine (AASK; ALLHAT; FACET), and
The effect of CCBs on MI was not significantly different from that
two administered felodipine (STOP-Hypertension-2), or nisoldipine
of diuretics (5 trials with 34,072 participants: RR 1.00, 95% CI 0.92
(ABCD) and one gave nifedipine (J-MIC(B)). One study did not
to 1.08, I2 = 0%; moderate-certainty evidence); beta-blockers (3 describe the the specific ACE inhibitors and CCBs that were used
trials with 22,249 participants: RR 0.90, 95% CI 0.79 to 1.02, I2 (HOMED-BP). The pooled RR for the trials comparing amlodipine
= 0%; moderate-certainty evidence); diuretics and beta-blockers and ACE inhibitors was 1.00 (95% CI 0.91 to 1.10, I2 = 0%; low-
(3 trials with 31,892 participants: RR 1.05, 95% CI 0.93 to 1.19, certainty evidence) (Analysis 2.2).
I2 = 72%; moderate-certainty evidence); and ACE inhibitors (7
trials with 27,999 participants: RR 1.05, 95% CI 0.97 to 1.14], I2 = Stroke (non-fatal and fatal stroke)
66%; low-certainty evidence). The incidence of MI was statistically
The incidence of stroke was not significantly different between CCB
significantly lower (P = 0.004) for CCBs compared to ARBs (6 trials
and diuretic groups (5 trials with 34,072 participants: RR 0.94, 95%
with 25,611 participants: RR 0.82, 95% CI 0.72 to 0.94, I2 = 0%;
CI 0.84 to 1.05, I2 = 0%; moderate-certainty evidence) or between
moderate-certainty evidence) (Analysis 2.1).
CCB and diuretic and beta-blocker groups (3 trials with 31,892
We found significant statistical heterogeneity between trials participants: RR 0.92, 95% CI 0.81 to 1.03, I2 = 55%; moderate-
comparing CCBs to diuretics and beta-blockers (I2 = 72%, P = certainty evidence). Hypertensive participants treated with CCBs
0.03) and CCBs to ACE inhibitors (I2 = 66%, P = 0.007). A possible had a significantly lower risk of developing a stroke than those
explanation for the heterogeneity may be that the type of CCB treated with a beta-blocker (3 trials with 22,249 participants: RR
studied was different in each trial. The three trials involving 0.77, 95% CI 0.67 to 0.88, I2 = 0%; moderate-certainty evidence)
diuretics and beta-blockers respectively studied an aralkylamine or an ACE inhibitor (7 trials with 27,999 participants: RR 0.90, 95%
derivative (verapamil, CONVINCE), a benzothiazepine derivative CI 0.81 to 0.99, I2 = 28%; low-certainty evidence). There was no
(diltiazem, NORDIL), and a DHP (felodipine, STOP-Hypertension-2). difference in risk of stroke between on CCB and ARB groups (6 trials
Another possible explanation is difference in participants. In with 25611 participants: RR 0.87, 95% CI 0.76 to 1.00, p = 0.05, I2 =
the CONVINCE trial, participants diagnosed as having hypertension 15%; moderate-certainty evidence) (Analysis 3.1), but the incidence
and who had one or more additional risk factors for cardiovascular of stroke was lower for amlodipine compared to ARBs (5 trials with
disease were enrolled, but participants enrolled in the other two 23265 participants:RR 0.85, 95% CI 0.74 to 0.98, I2 = 0%)(Analysis
trials had no additional risk factors for cardiovascular disease. Six 3.2; Figure 5).
Informed decisions.
Figure 5. Forest plot of comparison: 3 Stroke, outcome: 3.1 CCBs versus other classes of antihypertensive agents.


ALLHAT 377 9048 675 15255 80.3% 0.94 [0.83 , 1.07]
INSIGHT 67 3289 74 3286 11.8% 0.90 [0.65 , 1.25]
MIDAS 6 442 3 441 0.5% 2.00 [0.50 , 7.93]
NICS-EH 6 215 8 214 1.3% 0.75 [0.26 , 2.12]
SHELL 37 942 38 940 6.1% 0.97 [0.62 , 1.51]
Subtotal (95% CI) 13936 20136 100.0% 0.94 [0.84 , 1.05]

AASK 9 217 23 441 3.4% 0.80 [0.37 , 1.69]
ASCOT-BPLA 327 9639 422 9618 93.5% 0.77 [0.67 , 0.89]
ELSA 9 1177 14 1157 3.1% 0.63 [0.27 , 1.45]
Subtotal (95% CI) 11033 11216 100.0% 0.77 [0.67 , 0.88]

CONVINCE 133 8241 118 8361 21.4% 1.14 [0.89 , 1.46]
NORDIL 159 5410 196 5471 35.6% 0.82 [0.67 , 1.01]
Subtotal (95% CI) 15847 16045 100.0% 0.92 [0.81 , 1.03]

AASK 9 217 23 436 2.1% 0.79 [0.37 , 1.67]
ABCD 11 235 7 235 1.0% 1.57 [0.62 , 3.98]
ALLHAT 377 9048 457 9054 63.0% 0.83 [0.72 , 0.94]
FACET 10 191 4 189 0.6% 2.47 [0.79 , 7.75]
HOMED-BP 16 1171 11 1172 1.5% 1.46 [0.68 , 3.12]
J-MIC(B) 16 828 16 822 2.2% 0.99 [0.50 , 1.97]
Subtotal (95% CI) 13886 14113 100.0% 0.90 [0.81 , 0.99]
3.1.5 CCBs vs ARBs

CASE-J 47 2349 60 2354 13.7% 0.79 [0.54 , 1.15]
HOMED-BP 16 1171 9 1175 2.1% 1.78 [0.79 , 4.02]
IDNT 15 567 28 579 6.3% 0.55 [0.30 , 1.01]
NAGOYA 11 575 10 575 2.3% 1.10 [0.47 , 2.57]
VALUE 281 7596 322 7649 73.3% 0.88 [0.75 , 1.03]
VART 10 511 10 510 2.3% 1.00 [0.42 , 2.38]
Subtotal (95% CI) 12769 12842 100.0% 0.87 [0.76 , 1.00]
Informed decisions.
0.2 0.5 1 2 5
The reason for significant statistical heterogeneity between trials protocol, as we judged it to be important and it was reported in
comparing CCBs to diuretics and beta-blockers (I2 = 55%, P = 0.11) most of the included trials.
might be related to the type of CCBs, similar to the description
above in the MI results. Explanation for the heterogeneity may be We found only a marginally lower cardiovascular mortality in the
that the type of CCB studied and inclusion criteria of participants CCBs group compared to the beta-blocker group (4 trials with
were different in each trial. Regarding trials comparing CCBs to 44,825 participants: RR 0.90, 95% CI 0.81 to 0.99, I2 = 62%; low-
ARBs, one trial did not describe the specific CCBs used (HOMED-BP), certainty evidence). The effect of CCBs on cardiovascular mortality
whilst five of six trials gave participants amlodipine (CASE-J; IDNT; was not significantly different from that of diuretics (4 trials with
NAGOYA; VALUE; VART). The pooled RR for the trials comparing 32721 participants: RR 1.02, 95% CI 0.93 to 1.12, I2 = 0%; moderate-
amlodipine to ARBs was 0.85 (95% CI 0.74 to 0.98, I2 = 0%) (Analysis certainty evidence); diuretics and beta-blockers (3 trials with 31892
3.2). participants: RR 1.04, 95% CI 0.92 to 1.18, I2 = 0%); ACE inhibitors
(6 trials with 27619 participants: RR 0.98, 95% CI 0.89 to 1.07, I2
Congestive heart failure = 0%; moderate-certainty evidence) or ARBs (3 trials with 4642
There was no significant difference in development of congestive participants: RR 0.79, 95% CI 0.54 to 1.15, I2 = 0%; moderate-
heart failure between CCB and beta-blocker groups (2 trials with certainty evidence) (Analysis 5.1)
19,915 participants: RR 0.83, 95% CI 0.67 to 1.04, I2 = 0%; low-
The heterogeneity amongst trials involving beta-blockers (I2 = 62%,
certainty evidence) and between CCB and diuretic and beta-
P = 0.05) might be explained by the different types of CCBs that were
blocker groups (3 trials with 31,892 participants: RR 1.15, 95%
evaluated: a non-DHP in the INVEST trial (verapamil) and a DHP in
CI 0.99 to 1.33, I2 = 0%; low-certainty evidence). However, the
the other three trials (amlodipine in AASK and ASCOT-BPLA, and
risk of developing congestive heart failure was markedly higher
lacidipine in ELSA). After deselecting the INVEST trial, the pooled RR
in participants given CCBs than those given diuretics (5 trials
was 0.77 (95% CI 0.66 to 0.90, I2 = 0%), still showing a significant
with 34,072 participants: RR 1.37, 95% CI 1.25 to 1.51, I2 = 17%;
decrease in cardiovascular mortality in the CCB group (Analysis 5.2).
moderate-certainty evidence); ACE inhibitors (5 trials with 25,276
participants: RR 1.16, 95% CI 1.06 to 1.28, I2 = 0%; low-certainty Major cardiovascular events (MI, congestive heart failure,
evidence); and ARBs (5 trials with 23,265 participants: RR 1.20, 95% stroke, and cardiovascular mortality)
CI 1.06 to 1.36, I2 = 66%; low-certainty evidence) (Analysis 4.1).
Compared to beta-blockers, CCBs significantly reduced major
The lack of homogeneity between the five trials comparing a CCB to cardiovascular events (3 trials with 22,249 participants: RR 0.84,
an ARB may be due to the different inclusion criteria of participants: 95% CI 0.77 to 0.92, I2 = 0%). In contrast, when compared to
the IDNT trial included hypertensive individuals with type 2 diuretics, CCBs probably increased major cardiovascular events (4
diabetic nephropathy, and the NAGOYA trial included hypertensive trials with 33,643 participants: RR 1.05, 95% CI 1.00 to 1.09, I2 =
individuals with glucose intolerance, whilst the VALUE, CASE-J, 0%, P = 0.03). There was no significant difference in total major
and VART trials only required participants to have hypertension cardiovascular events when CCBs were compared to diuretics or
and cardiovascular risk factors. There was a significant increase in beta-blockers (2 trials with 21,011 participants: RR 1.02, 95% CI 0.95
congestive heart failure events among the diabetic nephropathic to 1.10, I2 = 0%); to ACE inhibitors (5 trials with 25,186 participants:
participants in IDNT (RR 1.58, 95% CI 1.17 to 2.14) and glucose RR 0.98, 95% CI 0.94 to 1.02, I2 = 45%); or ARBs (3 trials with 6874
intolerance participants in NAGOYA (RR 5.00, 95% CI 1.46 to 17.18]) participants: RR 0.97, 95% CI 0.78 to 1.22, I2 = 32%) (Analysis 6.1;
treated with a CCB compared to those treated with an ARB. Figure 6).
Cardiovascular mortality
We added death caused by cardiovascular disease as a
supplemental outcome, which differed from the published
Informed decisions.
Figure 6. Forest plot of comparison: 6 Major cardiovascular events, outcome: 6.1 CCBs versus other classes of
antihypertensive agents.


ALLHAT 2432 9048 3941 15255 91.2% 1.04 [1.00 , 1.09]
INSIGHT 200 3289 182 3286 5.7% 1.10 [0.90 , 1.33]
MIDAS 25 442 14 441 0.4% 1.78 [0.94 , 3.38]
SHELL 90 942 88 940 2.7% 1.02 [0.77 , 1.35]
Subtotal (95% CI) 13721 19922 100.0% 1.05 [1.00 , 1.09]

AASK 23 217 65 441 4.2% 0.72 [0.46 , 1.12]
ASCOT-BPLA 796 9639 937 9618 92.5% 0.85 [0.77 , 0.93]
ELSA 27 1177 33 1157 3.3% 0.80 [0.49 , 1.33]
Subtotal (95% CI) 11033 11216 100.0% 0.84 [0.77 , 0.92]
Test for overall effect: Z = 3.90 (P < 0.0001)
6.1.3 CCBs vs diuretics and β-blockers

CONVINCE 793 8241 775 8361 62.7% 1.04 [0.94 , 1.14]
Subtotal (95% CI) 10437 10574 100.0% 1.02 [0.95 , 1.10]

AASK 23 217 61 436 1.3% 0.76 [0.48 , 1.19]
ALLHAT 2432 9048 2514 9054 82.5% 0.97 [0.92 , 1.02]
FACET 27 191 14 189 0.5% 1.91 [1.03 , 3.52]
J-MIC(B) 50 828 44 822 1.4% 1.13 [0.76 , 1.67]
Subtotal (95% CI) 12480 12706 100.0% 0.98 [0.94 , 1.02]
6.1.5 CCBs vs ARBs

CASE-J 96 2349 108 2354 72.0% 0.89 [0.68 , 1.17]
NAGOYA 38 575 27 575 18.0% 1.41 [0.87 , 2.27]
VART 12 511 15 510 10.0% 0.80 [0.38 , 1.69]
Subtotal (95% CI) 3435 3439 100.0% 0.97 [0.78 , 1.22]
0.7 0.85 1 1.2 1.5

The poor methodological quality of the FACET trial might be a trials with 24,806 participants: RR 0.98, 95% CI 0.94 to 1.02, I2 = 0%)
source of heterogeneity amongst the five trials comparing CCBs (Analysis 6.2).
with ACE inhibitors. We undertook a sensitivity analysis on this
effect by deselecting the FACET trial; the results were unchanged (4
Informed decisions.
Systolic and diastolic BP reduction ACE inhibitors (low-certainty evidence) and ARBs (low-certainty
evidence) is robust after more RCTs were included in this update.
Using the weighted mean difference method and the fixed-effect
The other significant differences found were that first-line CCBs
model, we found that the mean systolic BP reduction of the CCB
reduced stroke more than ACE inhibitors (low-certainty evidence)
group was 0.81 mmHg (95% CI 0.56 to 1.06) less than that of the
and reduced MI more than ARBs (moderate-certainty evidence).
diuretic-based regimen group, and 3.00 mmHg (95% CI 2.59 to
With the inclusion of new studies comparing CCBs with ARBs, the
3.41) less than the diuretic-and-beta-blocker-based regimen group.
advantages of CCBs in reducing stroke over ARBs that were found in
Systolic BP reduction was -1.11 mmHg (95% CI −1.40 to −0.82)
the first version of the review no longer exist (Summary of findings
more with CCBs than with ACE inhibitors, and -2.10 mmHg (95%
1; Summary of findings 2; Summary of findings 3; Summary of
CI −2.46 to −1.74]) more than with ARBs. There was no significant
findings 4), but in pooled analysis, the incidence of stroke was lower
difference between the CCB group and beta-blocker group (P =
for amlodipine compared to ARBs.(Analysis 3.2)
0.38), or between the CCB group and alpha-1-antagonist group (P =
0.27) (Analysis 7.1). Blood pressures decreased in all treatment arms of all the
included trials, but mean BP reduction differed. First-line CCB-
For diastolic BP, the mean reduction of the CCB group was −0.68
based regimens lowered systolic BP less than first-line diuretic-
mmHg (95% CI −0.84 to −0.52) more than the diuretic group; −0.63
based regimens and conventional treatment-based regimens. In
mmHg (95% CI −0.81 to −0.44) more than the ACE inhibitor group;
contrast, first-line CCBs lowered diastolic BP better than diuretic-
−1.70 mmHg (95% CI −1.91 to −1.49) more than the ARB group;
based regimens. First-line CCB-based regimens also lowered both
and −1.20 mmHg (95% CI −2.39 to −0.01) more than the alpha-1-
systolic and diastolic BPs more than ACE inhibitors and ARBs. This
antagonist group. Mean diastolic changes between the CCB and
could partially explain the differences in stroke outcomes.
beta-blocker groups were not significantly different (Analysis 7.2).
Overall completeness and applicability of evidence
There was heterogeneity (I2 of 85%) for the four trials comparing
the effect of CCBs versus ACE inhibitors on systolic BP reduction, Most of the included trials with the exception of TOMHS
however there was no heterogeneity for the same comparison reported relevant hypertension outcomes, but not all of the
evaluating diastolic BP reduction. The heterogeneity was most desired outcomes were available from each trial. Furthermore,
likely due to the poor methodological quality of the FACET trial. supplemental inclusion criteria were required in several trials, and
Sensitivity analyses conducted without the FACET trial resulted in most trials were event-driven hypertension studies, which meant
homogeneous significant mean differences for both systolic and that the included participants tended to have more complicated
diastolic BP: mean difference −1.00 (95% CI −1.29 to −0.70) and hypertension or advanced disease (Zanchetti 2005). Patients at the
−0.62 (95% CI −0.81 to −0.44), respectively (Analysis 7.3). two extremes, that is those with uncomplicated hypertension at
one extreme and those with severe or acute hypertension and
DISCUSSION secondary hypertension at the other extreme, were not included in
the current analysis.
Summary of main results
Although we included 23 studies with a large number of
After a systematic search and selection process according to
participants comparing several classes of antihypertensive drugs
the protocol for this review, we included 23 RCTs with 153,849
in this update, the number of trials for each of the subgroups
participants that assessed cardiovascular outcomes or BP change,
was limited. Because of this data were insufficient for some
or both, among hypertensive participants. The two most important
comparisons. This was particularly the case for alpha-1-
outcomes from the perspective of the patient were total all-cause
antagonists. Furthermore, most of the included CCBs were
mortality and major cardiovascular events. The latter outcome
dihydropyridines, with evidence for non-DHPs inadequate.
is important as it is a composite of the individual outcomes of
stroke, MI, and congestive heart failure. There was no significant The prevalence of hypertension amongst adults with diabetes
difference between first-line CCBs and any of the other classes mellitus is approximately 80% (Kannel 1991). Although all major
of antihypertensive drugs for total mortality. In this update, no antihypertensive drug classes (i.e. ACE inhibitors, ARBs, CCBs,
new trial comparing CCBs with beta-blockers or diuretics has been and diuretics) are useful in the treatment of hypertension in
incorporated, therefore the outcomes for these comparisons are diabetes mellitus (Whelton 2018), guidelines recommended CCBs
consistent with the first version of the review. First-line CCBs as a first-line choice for those with hypertension and diabetes
reduced major cardiovascular events as compared to beta-blockers (JNC-8; Whelton 2018; Williams 2018). Opie and colleagues made
(moderate-certainty evidence) and increased major cardiovascular the point that the incidence of developing diabetes was less on
events as compared to diuretics (moderate-certainty evidence). the amlodipine-based regimen (Opie 2002). On the other hand,
The reduction in major cardiovascular events with CCBs as the NAGOYA study found that hypertensive participants with type
compared to beta-blockers is explained by a significant reduction in 2 diabetes mellitus or impaired glucose tolerance in the valsartan
stroke (moderate-certainty evidence) and cardiovascular mortality group had a significantly lower incidence of heart failure than
(low-certainty evidence). The increase in major cardiovascular those in the amlodipine group. A meta-analysis of RCTs of primary
events for first-line CCBs as compared to diuretics is explained prevention of albuminuria in participants with diabetes mellitus
by increased congestive heart failure events (moderate-certainty demonstrated a significant reduction in progression of moderately
evidence). The risk difference (RD) for heart failure for the to severely increased albuminuria with the use of ACE inhibitors or
comparison of CCBs versus diuretics was 0.02 and is thus clinically ARBs (Palmer 2015), with CCB showing no effect. As we were unable
important and consistent with either a protective effect of diuretics to extract data to separately evaluate the effects on hypertensive
or a harmful effect of CCBs for this outcome. The finding that participants with diabetes in our review, it is not possible to
first-line CCBs increased congestive heart failure as compared to
Informed decisions.
say whether CCBs have different effects in diabetic hypertensive other antihypertensive drugs (NICS-EH), and it concluded that
patients. the CCB and diuretic groups had a similar decrease in BPs and
cardiovascular events. BP differences between different classes of
Quality of the evidence drugs could have an impact on outcomes (Staessen 2003; Wright
2018), which is a further limitation of this type of review. In addition,
We graded the overall quality of the evidence and developed
three included trials had a 2 X 3 design (AASK; ABCD; HOMED-BP).
'Summary of findings' tables, using GRADEpro GDTsoftware.
Participants were randomised 1) BP tight target versus usual 2)
We found moderate-certainty evidence that all-cause mortality different drug classes. As reported, the effect of different drugs is
was not different between first-line CCBs and any other difficult to differentiate from that of BP targets.
antihypertensive classes.
We have tried to reduce the risk of attrition bias by reporting
We found moderate-certainty evidence that first-line CCBs on the intent-to-treat population to the greatest degree possible.
increased congestive heart failure more than diuretics, and low- We do not think publication bias is likely as we have done an
certainty evidence that they increased congestive heart failure extensive search of the pertinent literature, including published
more than ACE inhibitors or ARBs. and unpublished studies, without any language restrictions.
We found moderate-certainty evidence that first-line CCBs Agreements and disagreements with other studies or
reduced stroke, and low-certainty evidence that they reduced reviews
cardiovascular mortality more than beta-blockers.
This review was not designed to assess the effect of CCBs versus
We found low-certainty evidence that first-line CCBs reduced stroke placebo or no treatment, but other meta-analyses have addressed
more than ACE inhibitors, and moderate-certainty evidence that this question and demonstrated that first-line CCBs reduce stroke
they reduced myocardial infarction more than ARBs. and total cardiovascular events. A recent meta-analysis of 10 RCTs
(30, 359 participants) comparing CCBs blood pressure-lowering
Potential biases in the review process treatment with no or less intense treatment showed that significant
reductions in stroke, major cardiovascular events, cardiovascular
The included trials varied in their designs and methods, baseline and all-cause death were obtained with CCBs (Thomopoulos 2015).
and goal BPs, study populations, and drugs, so combining their Another meta-analysis of 147 RCTs including 464,000 participants
data to arrive at a conclusion may have some limitations. For with hypertension demonstrated that all major antihypertensive
example, CCBs are a heterogeneous group of drugs that are drug classes (diuretics, ACE inhibitors, ARBs, beta-blockers, and
subclassified into DHPs and non-DHPs. The different classes have CCBs) caused a similar reduction in coronary heart disease events
different in binding sites on the calcium channel pores and thus and stroke for a given reduction in BP (Law 2009). Blood pressure
could have different effects (Opie 2000; Triggle 2007). In the current lowering by all classes of antihypertensive drugs is accompanied
review, we did not evaluate different types of CCBs in separate by significant reductions in stroke and major cardiovascular events,
comparisons, but it might not be appropriate to combine them supporting the concept that reduction of these events is due to BP
in a meta-analysis. The high I2 values for pooled trials involving lowering.
both DHPs and non-DHPs (72% for three trials assessing MI events)
are consistent with this possibility (CONVINCE; NORDIL; STOP- In this review, we found that CCBs increased total cardiovascular
Hypertension-2). However, in this case dividing the trials into events as compared to diuretics; within total cardiovascular events,
DHPs and non-DHPs does not explain the heterogeneity. Likewise, only congestive heart failure events increased with CCB. The
heterogenous populations in the included trials might be the results of recent meta-analyses are consistent with this conclusion:
cause of the heterogeneity of the effect. In the current review, thiazides were associated with a lower risk of heart failure
enrolled participants included those with diabetes, cardiovascular compared with CCBs, whilst there was no difference between
disease, kidney disease, or other conditions. It was not possible to groups in other events (Reboussin 2017; Thomopoulos 2015).
investigate the effect of these subgroup populations on the effect The increase in total cardiovascular events for first-line CCBs as
size. In general, there was excellent homogeneity of most effects as compared to diuretics is explained by increased congestive heart
shown by an I2 value of 0%, with only a few outcomes associated failure events with CCBs.
with I2 > 50%, leading us to believe that the overall conclusions of
our review are valid. CCBs significantly increased the risk of congestive heart failure
as compared to diuretics, ACE inhibitors, and ARBs. This
Although the benefits of BP lowering for the prevention of finding is consistent with other reviews (Black 2004; Opie 2000;
cardiovascular disease are well established (BPLTTC 2000; BPLTTC Thomopoulos 2015). The Systematic Review for the 2017 ACC/
2003; Ezzati 2002; Thomopoulos 2015; Wright 2018; Xie 2016), AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline
which antihypertensive drug class should be prescribed first is still for the Prevention, Detection, Evaluation, and Management of High
somewhat controversial. In order to achieve the BP goal many Blood Pressure in Adults indicated that thiazides were associated
patients need to be prescribed more than one antihypertensive with a lower risk of many cardiovascular outcomes compared with
agent (Chobanian 2003; Haller 2008; Mancia 2007). This fact leads to other antihypertensive drug classes (Reboussin 2017). Since CCBs
another limitation in the review and is perhaps its major weakness. and other drug classes did not have any other advantages as
Since additional antihypertensive agents other than first-line drugs compared to diuretics, this would suggest that diuretics are the
were administered sequentially to reach BP goals in most of the preferred first-line drugs for patients with hypertension.
included trials, the results may have been confounded, although
they were presumed to reflect the effect of the first drug. Only The results of this review are consistent with the findings of
one small trial included in our review prohibited the use of any another Cochrane Review evaluating the comparison of beta-
Informed decisions.
blockers versus first-line CCBs (Wiysonge 2007). That review total mortality as compared to other antihypertensive drug classes.
concluded that beta-blockers reduced total cardiovascular events First-line CCBs reduce major cardiovascular events, stroke, and
significantly less than CCBs. A similar meta-analysis including six cardiovascular mortality as compared to beta-blockers. First-line
of the trials included in our review, INSIGHT; MIDAS; NICS-EH; CCBs increase major cardiovascular and congestive heart failure
NORDIL; STOP-Hypertension-2; VHAS, concluded that mortality events as compared to diuretics. First-line CCBs reduce stroke
and major cardiovascular events with CCBs were similar to those as compared to angiotensin-converting enzyme (ACE) inhibitors
seen with conventional therapy (diuretics or beta-blockers) (Opie and myocardial infarction as compared to angiotensin receptor
2002). A recent meta-analysis showed that the risk of stroke was blockers (ARBs), but they increase congestive heart failure events
significantly higher (25%) with beta-blockers as compared with as compared to both ACE inhibitors and ARBs.
CCBs (Thomopoulos 2015). To this point there is no evidence to
support the initial use of beta-blockers for hypertension in the The review shows an advantage of diuretics over CCBs in reducing
absence of specific cardiovascular comorbidities. major cardiovascular mortality and congestive heart failure events.
We found evidence supporting CCBs over beta-blockers in reduce
Other authors have claimed that CCBs are more effective than major cardiovascular events, stroke, and cardiovascular mortality.
other treatments in decreasing the risk of stroke in hypertensive It should be noted that many of the differences found in the
individuals (Angeli 2004; Verdecchia 2005). However, a previous current review are not robust, and further trials might change the
meta-analysis found no difference between ARBs and CCBs in conclusions. It will therefore be important to follow the research
risk of stroke in diabetic participants (Turnbull 2005). Our results in this field closely and update this review when new data become
showed that stroke events are significantly reduced by CCBs as available.
compared to beta-blockers and ACE inhibitors. In the previous
version of this review we found that CCBs reduced the risk of Implications for research
stroke as compared to ARBs (2 trials with 16,391 participants). In
More well-designed randomised controlled trials comparing CCBs
this updated version we added 4 new trials for comparison (CASE-
with other types of antihypertensive drugs and combinations
J; HOMED-BP; NAGOYA; VART),the results indicated no difference
of CCBs with other antihypertensive drug classes are needed,
between ARBs and CCBs(total 6 trials with 25611 participants). But
especially for individuals with comorbidities such as diabetes,
in a pooled analysis of 5 trials comparing amlodipine of CCBs and
coronary heart disease, and nephropathy. These trials must avoid
ARBs, the incidence of stroke was lower for amlodipine compared
confounding factors to the greatest degree possible, such as by
to ARBs.This may be due to the greater blood pressure-lowering
ensuring that the secondary drugs added to each arm of the trial are
effect of CCBs as compared to ACE inhibitors as was found in this
the same. It is important that all relevant outcomes are well defined
review, but it does not explain the difference for beta-blockers,
and reported.
which did not have a different blood pressure-lowering effect. It
has been hypothesised that CCBs might have anti-atherosclerotic ACKNOWLEDGEMENTS
actions that could be helpful in reducing stroke as well (Angeli
2004). We would like to acknowledge the original authors of this Cochrane
Review protocol (Onder G, Furberg CD, Moore A, Psaty BM, Pahor
AUTHORS' CONCLUSIONS M), who identified the topic and contributed extensively to the
background.
Implications for practice
This update changed some conclusions of the previous version of
this review. First-line calcium channel blockers (CCBs) do not affect
Informed decisions.
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INVEST {published data only} hypertensives. Hypertension 1999;34(5):1129-33.
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* Hansson L, Lindholm LH, Ekbom T, Dahlöf B, Lanke J,

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antihypertensive drugs in elderly patients: cardiovascular Abascal 1998 {published data only}
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Mascioli SR, Grimm RH Jr, Neaton JD, Stamler J, Prineas RJ, plasma aldosterone, albuminuria, and urinary liver-type fatty
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of calcium channel or β-blockade on the progression of
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valsartan or amlodipine: the VALUE randomised trial. Lancet Xue C, Zhou C, Yang B, Lv J, Dai B, Yu S, et al. Comparison
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Leon 1993 {published data only} Schneider 1991 {published data only}
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Mesci 2011 {published data only} Liu L, Wang JG, Gong L, Liu G, Staessen JA. Comparison of
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Kim-Mitsuyama S, Ogawa H, Matsui K, Jinnouchi T, Jinnouchi H, Amery A, Birkenhäger W, Bulpitt CJ, Clément D, De Leeuw P,
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* Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
AASK
Methods Long-term, multicentre, randomised controlled, double-blind trial, using a 3 × 2 factorial design. Be-
cause of acute changes in glomerular filtration rate (GFR), the amlodipine arm was halted about 1 year
ahead of the protocol, while most participants in other groups were followed to the planned end, giv-
ing a median follow-up of 4.3 years to the cardiovascular composite outcome. All analyses were in-
tent-to-treat.
Participants Participants (N = 1094) were self-identified African-Americans with hypertension (diastolic blood pres-
sure (BP) was 95 mmHg or higher), aged 18 to 70 years, with glomerular filtration rate (GFR) between 20
and 65 mL/min per 1.73 m2.
Interventions Participants were randomised equally to 1 of 2 blood pressure goals (usual mean arterial pressure
(MAP) goal of 102 to 107 mmHg (N = 554) or a lower MAP goal of 92 mmHg (N = 540)), and to treatment
with 1 of 3 antihypertensive drugs (metoprolol, 50 to 200 mg/d (N = 441); ramipril, 2.5 to 10 mg/d (N =
436); or a dihydropyridine calcium channel blocker (CCB) amlodipine, 5 to 10 mg/d (N = 217), using a
2:2:1 randomisation ratio). Additional open-labeled antihypertensives were added if the BP goal could
not be achieved by the randomised drug.
Outcomes Rate of change in GFR and other renal outcomes, and all cardiovascular events including cardiovascu-
lar deaths and hospitalisations for miocardial infarction (MI), strokes, heart failure, revascularisation
procedures, and other hospitalised cardiovascular events were reviewed.
Notes Study was carried out at 11 clinical centres in the USA.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk The randomisation was stratified by city using randomly permuted blocks, and
tion (selection bias) the Data Coordinating Center performed randomisation centrally.
Allocation concealment Unclear risk Method of allocation concealment was not described.
(selection bias)
Blinding (performance Low risk Participants and investigators were masked to randomised drug but not blood
bias and detection bias) pressure goal.
All outcomes
Incomplete outcome data Low risk Missing data were equal amongst the treatment groups, and an intention-to-
(attrition bias) treat analysis was performed.
All outcomes
Selective reporting (re- Low risk All outcomes listed in the methods section were reported.
porting bias)
Other bias Low risk No other potential bias was found.
Informed decisions.
ABCD
Methods A prospective, controlled, randomised, double-blinded trial with a long-term follow-up of more than 5
years. Cardiovascular endpoints were analysed using the intention-to-treat principle.
Participants Enrolled participants were diagnosed with non-insulin-dependent diabetes mellitus (NIDDM), and had
diastolic blood pressure of 80 mmHg or higher and were receiving no antihypertensive medications at
the time of randomisation. The current review only focused on the hypertensive cohort (N = 470) (mean
baseline diastolic blood pressure ≥ 90 mmHg).
Interventions Participants randomised to active study medication received either nisoldipine (N = 235) (10 mg per
day, with increases to 20, 40, and 60 mg per day, plus placebo for enalapril) or enalapril (N = 235) (5 mg
per day, with increases to 10, 20, and 40 mg per day, plus placebo for nisoldipine). Open-label antihy-
pertensive medications except the study drugs were added when necessary.
Outcomes Cardiovascular outcomes including death due to cardiovascular events, non-fatal myocardial infarc-
tion (MI), non-fatal cerebrovascular accident (CVA), heart failure requiring hospital admission, and pul-
monary infarction were reviewed.
Notes Results at the end of the planned 5-year follow-up were reported in 1998, and additional follow-up re-
sults were described in 2000.
Risk of bias
Random sequence genera- Unclear risk Method of sequence generation was not described.
tion (selection bias)
Allocation concealment Unclear risk Method of concealment was not described.

(selection bias)
Blinding (performance Low risk Study drug in each group plus placebo for the other study drug were adminis-
bias and detection bias) tered in a double-blind manner.
All outcomes
Incomplete outcome data Low risk Missing data were equal between the treatment groups, and an intention-to-
All outcomes
porting bias)
ALLHAT
Methods A randomised, double-blind, multicentre clinical trial with a large sample size and long follow-up (with
a mean length of 4.9 years (standard deviation (SD) 1.4 years)).
Informed decisions.
ALLHAT (Continued)
Participants Participants (N = 33,357) were men and women aged 55 years or older who had stage 1 or stage 2 hyper-
tension with at least 1 additional risk factor for coronary heart disease (CHD) events.
Interventions Treatment with the study drug was initiated the day after randomisation. Participants were randomly
assigned to chlortalidone, amlodipine, or lisinopril in a ratio of 1.7:1:1, which meant that 15,255, 9048,
and 9054 participants were enrolled in the 3 groups, respectively. Goal blood pressure was less than
140/90 mmHg achieved by titrating the assigned study drug, with additional open-label agents allowed
if necessary.
Outcomes The primary outcome was fatal CHD or non-fatal myocardial infarction combined; secondary outcomes
included all-cause mortality, stroke, combined CHD, and combined cardiovascular disease.
Notes Sponsored by the National Heart, Lung, and Blood Institute and carried out in 623 North American cen-
tres.
Risk of bias
Random sequence genera- Low risk Randomisation scheme was generated by computer.
Allocation concealment Low risk It specified that the concealed randomisation scheme was implemented at the
(selection bias) clinical trials centre and stratified by centre.
Blinding (performance Low risk Study drugs were encapsulated and identical in appearance.
bias and detection bias)
All outcomes
Incomplete outcome data Low risk 625 centres in the United States and Canada participated in the trial; 2 sites
(attrition bias) were excluded because their 30 participants had poor documentation of
All outcomes informed consent. Participants were recruited in 623 centres, which might
have impacted on the results, however an intention-to-treat analysis was per-
formed.
porting bias)
ASCOT-BPLA
Methods An independent, investigator-initiated, investigator-led, multicentre, prospective, randomised con-

trolled trial, with 5.5 years' median follow-up. It compared the time to first event on an intention-to-
treat basis.
Participants A total of 19,257 participants aged 40 to 79 years were recruited, all of whom had either untreated hy-
pertension (systolic blood pressure ≥ 160 mmHg, diastolic BP ≥ 100 mmHg, or both) or treated hyper-
tension (systolic BP ≥ 140 mmHg, diastolic BP ≥ 90 mmHg, or both). Participants had to have at least 3
other cardiovascular risk factors.
Interventions Participants were randomised to CCB-based regimen (amlodipine 5 to 10 mg; N = 9639) or β-block-
er-based regimen (atenolol 50 to 100 mg; N = 9618). Additional antihypertensive agents were admin-
istered to both groups according to a prespecified algorithm: perindopril 4 to 8 mg was added to am-
Informed decisions.
ASCOT-BPLA (Continued)
lodipine-based group as required; bendroflumethiazide 1.25 to 2.5 mg was added to atenolol-based
group as required.
Outcomes Primary endpoints: non-fatal myocardial infarction (MI) + fatal coronary heart disease
Secondary endpoints: all-cause mortality, total stroke, primary endpoint minus silent MI, all coronary
events, total cardiovascular events and procedures, cardiovascular mortality, and non-fatal and fatal
heart failure
Tertiary endpoints: silent MI, unstable angina, chronic stable angina, peripheral arterial disease, life-
threatening arrhythmias, development of diabetes, development of renal impairment
Notes Participants were recruited between February 1998 and May 2000 in the UK, Ireland, and the Nordic
countries.
Risk of bias
Random sequence genera- Low risk The randomisation was a computer-generated optimum allocation.
Allocation concealment Low risk The allocation was blinded for any person involved in the undertaking of the
(selection bias) study.
Blinding (performance Low risk A PROBE design was used.

All outcomes
Incomplete outcome data Low risk 2 centres with 85 participants were excluded after randomisation, but miss-
(attrition bias) ing data were equal between the treatment groups, and an intention-to-treat
All outcomes analysis was performed.
porting bias)
CASE-J
Methods A prospective, multicentre, randomised, open-label, active-controlled, 2-arm parallel-group compari-

son with a response-dependent dose titration and blinded assessment of the endpoints. Participants
were followed for an average of 3.2 years.
Participants 4728 hypertension patients (systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure
(DBP) ≥ 90 mmHg in participants < 70 years old or SBP ≥ 160 mmHg or DBP ≥ 90 mmHg in participants ≥
70 years old) with high risk (high-risk patients were defined by the presence of any of the following fac-
tors: (1) severe hypertension (SBP ≥ 180 mmHg or DBP ≥ 110 mmHg); (2) type 2 diabetes mellitus; (3) a
history of stroke or transient ischaemic attack > 6 months before the screening; (4) left ventricular hy-
pertrophy; (5) proteinuria or a serum creatinine concentration ≥ 1.3 mg/dL; or (6) arteriosclerotic pe-
ripheral artery obstruction) were enrolled in the study. Mean age was 63.8 years, and 136 participants
were lost to follow-up.
Interventions Participants were randomly assigned to the treatment groups. Enrolled participants were given can-
desartan cilexetil or amlodipine besylate. The candesartan was administered orally at a dose of 4 to
Informed decisions.
CASE-J (Continued)
8 mg/d and was increased to 12 mg/d when necessary. The amlodipine was administered orally at a
dose of 2.5 to 5.0 mg/d and was increased to 10.0 mg/d when necessary. Once a participant was giv-
en the assigned medication, use of other angiotensin receptor blockers (ARBS), CCBs, and all of the
angiotensin-converting enzyme inhibitors was prohibited. Participants already being treated with di-
uretics, α-blockers, β-blockers, or α- and β-blockers before enrolment were allowed to continue taking
these medications.
Outcomes Primary endpoint: sudden death, cerebrovascular events, cardiac events and vascular events.
Secondary endpoints: all-cause death and new-onset diabetes
Notes A large-scale clinical trial in Japan
Risk of bias
Random sequence genera- Low risk Participants were randomised by the Automatic Bar Code Data-Capturing/Al-
tion (selection bias) location, Booking & trial Coding, Data Management (ABCD) system.
Allocation concealment Low risk Centralised randomisation

(selection bias)
Blinding (performance Low risk Blinded assessment of the endpoint

All outcomes
Incomplete outcome data Low risk Missing data were almost equal between the treatment groups, and an inten-
(attrition bias) tion-to-treat analysis was performed.
All outcomes
porting bias)
CONVINCE
Methods Prospective, double-blind, randomised, active-controlled, multicentre, international clinical trial with a
mean follow-up of 3 years
Participants A total of 16,602 participants with hypertension and 1 or more additional risk factors for cardiovascu-
lar disease were enrolled, but 126 of them were excluded because of data integrity, so findings from
16,476 participants were reported.
Interventions Participants were administered standard-of-care drug (β-blocker or diuretic) chosen by the investi-
gator prior to randomisation. They were then randomised to verapamil group (N = 8241) (starting at
180 mg daily, with dose increased or other drugs added when necessary) or standard-of-care regimen
group (N = 8361) (β-blocker or diuretic).
Outcomes Effect in preventing acute myocardial infarction, stroke, or cardiovascular disease related death, and
all-cause mortality.
Informed decisions.
CONVINCE (Continued)
Notes Study was conducted at 661 clinical sites in 15 countries; the sponsor closed the study 2 years earlier
than the planned 5-year follow-up for commercial reasons.
Risk of bias
Random sequence genera- Low risk A simple automated system, the interactive voice response system, was used
tion (selection bias) for randomising, assigning, and tracking blinded medication.
Allocation concealment Low risk See above

(selection bias)
Blinding (performance Low risk Labeled bottles with active drug or placebo were given to participants; the
bias and detection bias) content of the bottles was blinded.
All outcomes
Incomplete outcome data Low risk Participants from 2 sites (n = 126; 62 randomised to controlled-onset extend-
(attrition bias) ed-release verapamil) were excluded because of data integrity concerns; the
All outcomes impact of these exclusions on the results was unclear, but we performed an in-
tention-to-treat analysis in the review.
porting bias)
Other bias Unclear risk Withdrawal between groups was imbalanced (115 with verapamil, 207 with
atenolol or hydrochlorothiazide).
ELSA
Methods A randomised, double-blind, multicentre trial with a mean follow-up of 3.75 years. 49 lacidipine and 43
atenolol participants lost to follow-up; an intention-to-treat analysis was performed.
Participants All enrolled participants (N = 2334) were aged 45 to 75 years with sitting systolic blood pressure of 150
to 210 mmHg and diastolic blood pressure of 95 to 115 mmHg.
Interventions Participants were randomised to receive either lacidipine 4 mg once daily (N = 1177) or atenolol 50
mg once daily (N = 1157). If diastolic blood pressure goal was not achieved, the dose of lacidipine
could be increased to 6 mg, and atenolol could be increased to 100 mg (month 1), with open-label hy-
drochlorothiazide added (12.5 mg daily month 3 and 25 mg daily month 6).
Outcomes Change in mean maximum intima-media thickness, proportion of participants with an increase or de-
crease in plaque number, incidence of cardiovascular events and total mortality
Notes Study was conducted in 410 clinical units in France, Germany, Greece, Italy, Spain, Sweden, and the UK.
Risk of bias
Random sequence genera- Low risk Randomisation was computer-generated.

Informed decisions.
ELSA (Continued)

(selection bias)
Blinding (performance Low risk Participants and study personnel, excluding the Safety Committee, were blind-
bias and detection bias) ed to treatment assignment for the duration of the study.
All outcomes
All outcomes
porting bias)
FACET
Methods An open-label, randomised prospective trial. Participants were followed for up to 3.5 years. All analyses
were intention-to-treat unless otherwise stated.
Participants Participants (N = 380) with a diagnosis of non-insulin-dependent diabetes mellitus and hypertension
(systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg)
Interventions Participants were randomly assigned to open-label fosinopril (20 mg/day) (N = 189) or amlodipine (10
mg/day) (N = 191). The other study drug was added when necessary.
Outcomes Serum lipids and diabetes control, cardiovascular events, blood pressure control, and renal function
status
Notes Participants were recruited from an outpatient diabetes clinic in Marino, Italy.
Risk of bias
Random sequence genera- Low risk Computer-generated random number sequence


(selection bias)
Blinding (performance High risk Study drugs were administered open-label.

All outcomes
All outcomes
porting bias)
Informed decisions.
FACET (Continued)
Other bias High risk When BP was not controlled well on monotherapy, the other study drug was
added. This could have affected the evaluation of effect of each study drug.
HOMED-BP
Methods A clinical trial with PROBE design, the last follow-up (median 5.3 years)
Participants This trial involved 3518 participants (50% women; mean age 59.6 years) with mild-to-moderate hyper-
tension who were 40 years of age or older.
Interventions Participants were randomised to usual control (125 to 134/80 to 84 mmHg) vs tight control (< 125/< 80
mmHg) of blood pressure self-measurement at home and to initiation of drug treatment with an an-
giotensin-converting enzyme inhibitor, angiotensin receptor blocker, or calcium channel blocker.
Outcomes The primary endpoint was cardiovascular death plus stroke and myocardial infarction.
Notes Participants were recruited from 457 general practices throughout Japan from 2001 to 2010.
Risk of bias
Random sequence genera- Low risk Randomisation was based on a computerised random number function with a
tion (selection bias) minimisation algorithm.

(selection bias)
Blinding (performance Low risk A prospective randomized open-blinded end point evaluation design was
bias and detection bias) used.
All outcomes
Incomplete outcome data Low risk Missing data were almost equal between the treatment groups, and an inten-
(attrition bias) tion-to-treat analysis was performed.
All outcomes
Selective reporting (re- Low risk All outcomes listed in the methods section were reported
porting bias)
IDNT
Methods An international, prospective, randomised, double-blind, placebo-controlled, multicentre trial. The

mean duration of follow-up was 2.6 years. 16 enrolled participants never received the study medica-
tion, and follow-up was incomplete in 11 participants; reasons were not specified. All analyses were
based on the intention-to-treat principle.
Informed decisions.
IDNT (Continued)
Participants A total of 1715 hypertensive participants (systolic blood pressure > 135 mmHg whilst sitting, diastolic
blood pressure > 85 mmHg whilst sitting, or documented treatment with antihypertensive agents) with
diabetic nephropathy due to type 2 diabetes mellitus underwent randomisation.
Interventions Eligible participants were randomised into 1 of 3 groups treated with irbesartan (300 mg daily) (N =
579), amlodipine (10 mg daily) (N = 567), or placebo (N = 569). The target blood pressure was 135/85
mmHg or less in all groups, and other classes of antihypertensive agents were allowed as needed in
each group.
Outcomes The primary endpoint was renal outcomes.
The secondary endpoint was the composite of fatal or non-fatal cardiovascular events, which were not
statistically different in the 3 groups.
Adverse events were recorded at quarterly visits.
Notes Conducted in 209 centres in the Americas, Europe, Israel, and Australasia by the clinical co-ordinating
centre and the various committees of the Collaborative Study Group.
Risk of bias
Random sequence genera- Low risk Adequate sequence was generated by computer.
Allocation concealment Low risk To minimise any centre effect, randomisation was blocked by centre.
(selection bias)
Blinding (performance Low risk Probably done because it was stated as a "double-blind clinical trial",
bias and detection bias) "matched placebo" was given in the control group, and the blinded clinical
All outcomes database was provided to the centre for statistical analyses.
All outcomes
porting bias)
INSIGHT
Methods A prospective, randomised, double-blind trial. Analysis was done by intention-to-treat. 254 partici-
pants were excluded after randomisation from centres due to misconduct, and were not included in
the analysis. The follow-up was 3 years.
Participants A total of 6575 participants aged 55 to 80 years with hypertension (BP ≥ 150/95 mmHg, or ≥ 160 mmHg
systolic) were enrolled. Participants also had at least 1 additional cardiovascular risk factor.
Interventions Participants were randomly assigned to nifedipine 30 mg in a long-acting gastrointestinal-transport

system formulation (n = 3289) or co-amilozide (hydrochlorothiazide 25 g plus amiloride 2.5 mg; n =
3286). Dose titration was by dose doubling, and addition of atenolol 25 to 50 mg or enalapril 5 to 10 mg.
Informed decisions.
INSIGHT (Continued)
Outcomes Cardiovascular death, MI, heart failure, or stroke
Notes Study was conducted in 703 centres in 8 countries in Western Europe and Israel.
Risk of bias

(selection bias)
Blinding (performance Low risk Identical placebo was administered at the same time of day.
All outcomes
Incomplete outcome data Unclear risk 254 participants (132 and 122 participants in each group) were excluded after
(attrition bias) randomisation from centres due to misconduct, and were not included in the
All outcomes analysis.
porting bias)
INVEST
Methods An international, multicentre study with a prospective, randomised, open blinded endpoint evaluation
design. Mean follow-up was 2.7 years. Intention-to-treat principle was used in analyses.
Participants A total of 22,576 hypertensive coronary artery disease (CAD) patients aged 50 years or older were en-
rolled.
Interventions Participants were randomly assigned to either verapamil sustained release (240 mg/d) (N = 11,267) or
atenolol (50 mg/d) (N = 11,309). Administration of additional antihypertensive agents was allowed to
achieve BP goals.
Outcomes Primary: all-cause mortality, non-fatal MI, or non-fatal stroke
Additional outcomes: time to most serious event, cardiovascular death, angina, cardiovascular hospi-
talisations, BP control, etc.
Notes Study recruited participants at 862 sites in 14 countries.
Risk of bias
Random sequence genera- Low risk An internet-based management system automatically randomised each par-
tion (selection bias) ticipant to a treatment strategy.
Informed decisions.
INVEST (Continued)
Allocation concealment High risk The randomisation result was stored in the central database, but drugs also
(selection bias) might be open-label because of the PROBE design.
Blinding (performance Low risk It used the blinded endpoint design.

All outcomes
All outcomes
porting bias)
J-MIC(B)
Methods A prospective, randomised controlled clinical trial comparing the effect of nifedipine retard versus
ACE inhibitors on the incidence of cardiac events and mortality due to cardiovascular disease. The fol-
low-up was 3 years, and analysis was done on an intention-to-treat basis.
Participants 1650 outpatients aged under 75 years with diagnoses of both hypertension and coronary artery disease
Interventions Participants in the nifedipine group received nifedipine retard (a long-acting nifedipine formulation
given at a dose of 10 to 20 mg twice daily in Japan) for 3 years, whilst participants in the ACE inhibitor
group received an ACE inhibitor (enalapril at 5 to 10 mg, imidapril at 5 to 10 mg, or lisinopril at 10 to 20
mg, once daily as recommended in Japan) for 3 years.
Outcomes The primary endpoint was the overall incidence of cardiac events (cardiac death or sudden death, my-
ocardial infarction, hospitalisation for angina pectoris or heart failure, serious arrhythmia, and coro-
nary interventions).
Notes Participants were enrolled at 354 Japanese hospitals specialising in the management of cardiovascular
disease between January 1994 and July 1997.
Risk of bias
Random sequence genera- Low risk A computer-generated random number sequence obtained from an external
tion (selection bias) biostatistician was used for randomisation.
Allocation concealment Low risk The sealed-envelope method was used for randomisation of the study drug.
(selection bias)
Blinding (performance Low risk Blinded endpoint design was used.

All outcomes
Incomplete outcome data Low risk Intention-to-treat analysis was performed.

(attrition bias)
All outcomes
Informed decisions.
J-MIC(B) (Continued)
porting bias)
MIDAS
Methods A multicentre, randomised, double-blind, controlled clinical trial with a follow-up of 3 years. All analy-
ses were performed using the intention-to-treat approach.
Participants Enrolled participants (N = 883) all had hypertension (average diastolic BP from 90 to 115 mmHg).
Interventions Participants were randomised into 2 treatment groups: hydrochlorothiazide, 12.5 to 25 mg twice a day
(n = 441) or isradipine, 2.5 to 5.0 mg twice a day (n = 442). If diastolic BP did not reach the planned goal
with the highest dose of the study drug, open-label enalapril was added.
Outcomes Mean maximum intima-media thickness, and other findings of carotid artery and vascular events/pro-
cedures
Notes Study was conducted in 9 medical centre clinics.
Risk of bias
Random sequence genera- Low risk The randomisation process was stratified and blocked by clinic.

(selection bias)
Blinding (performance Low risk Study was stated to be double-blind, but method of blinding was not de-
bias and detection bias) scribed.
All outcomes
All outcomes
porting bias)
NAGOYA
Methods A prospective, open-label, randomised controlled trial with a follow-up of 3.2 years. All analyses were
performed using the intention-to-treat approach.
Informed decisions.
NAGOYA (Continued)
Participants A total of 1150 participants (women: 34%; mean age: 63 years; diabetes mellitus: 82%) were enrolled.
Participants were aged between 30 and 75 years with both hypertension and glucose intolerance.
Interventions Participants were randomised into 2 treatment groups: valsartan 80 mg once daily (n = 575) or am-
lodipine 5 mg once daily (n = 575). Physicians could increase the respective dose until 160 mg or 10 mg
daily after 4 weeks, and other antihypertensive drugs could be added after 8 weeks as needed.
Outcomes Primary outcome was a composite of acute myocardial infarction, stroke, coronary revascularisation,
admission attributed to heart failure, or sudden cardiac death.
Notes Participants were recruited by 171 cardiologists only from 46 board-certified medical centres and hos-
pitals.
Risk of bias
Random sequence genera- Low risk Randomisation was performed automatically by a host computer system using
tion (selection bias) the minimisation method.

(selection bias)

All outcomes
All outcomes
porting bias)
Other bias Unclear risk No other potential bias was found.
NICS-EH
Methods A randomised, double-blind trial with a follow-up of 5 years
Participants Patients ≥ 60 years of age with systolic BP of 160 to 220 mmHg and diastolic BP<115 mmHg were en-
rolled (N = 429). Participants were without history of cardiovascular complications.
Interventions Participants were randomly assigned to 20 mg of sustained-release nicardipine hydrochloride twice

daily (N = 215) or 2 mg of trichlormethiazide once daily (N = 214). Doubling of the dose was permitted if
BP response was insufficient, but any other antihypertensive drugs were prohibited.
Outcomes Cardiovascular complications
Notes Study was conducted in Japan.
Risk of bias
Informed decisions.
NICS-EH (Continued)

(selection bias)
Blinding (performance Low risk It was stated as double-dummy, but details were not described.
All outcomes
Incomplete outcome data High risk Data for withdrawn participants were not included using intention-to-treat
(attrition bias) analysis, but we were able to obtain the missing data to include in our review.
All outcomes
porting bias)
NORDIL
Methods A prospective, randomised, open, blinded-endpoint, multicentre, parallel-group study. The mean fol-
low-up was 4.5 years, and 52 participants (0.5%) were lost to follow-up. Analysis was done by inten-
tion-to-treat.
Participants A total of 10,881 participants, aged 50 to 74 years, with diastolic BP of 100 mmHg or more on 2 occa-
sions, were enrolled.
Interventions Participants were randomised to a diltiazem-based regimen (180 to 360 mg daily, N = 5410) or conven-
tional antihypertensive treatment (N = 5471) with diuretics, β-blockers, or both. Additional antihyper-
tensive treatment could be given to any participant to lower diastolic BP to less than 90 mmHg.
Outcomes Stroke, MI, and other cardiovascular death
Notes Recruitment of participants was from 9 October 1992 to 31 October 1999 in 1032 health centres in Nor-
way and Sweden.
Risk of bias
Allocation concealment Low risk Method of concealment was not described, but risk of bias could be limited by
(selection bias) strict randomisation and blinded endpoint assessment.
Blinding (performance Low risk Blinded endpoint study, all endpoints were blinded before evaluation by the
bias and detection bias) separate endpoint committee.
All outcomes
Informed decisions.
NORDIL (Continued)
All outcomes
porting bias)
Other bias Unclear risk In the diltiazem group, a diuretic or -blocker was added in step 3, and any oth-
er antihypertensive compound could be added as step 4.
SHELL
Methods A randomised, controlled, multicentre trial conducted in outpatient clinics. Follow-up visits were made
at monthly intervals during the first 3 months after randomisation and thereafter after 6 months and
every year for a maximum of 5 years (median 32 months). Data were analysed on an intention-to-treat
basis by BETA Trial Center.
Participants Participants (N = 1882) were recruited if sitting systolic BP was 160 mmHg with a diastolic BP ≤ 95
mmHg.
Interventions Participants were randomly assigned to the administration of chlortalidone 12.5 mg/d (N = 940) or
lacidipine 4 mg/d (N = 942). Increased dose of study drug and additional antihypertensive agents could
be administered to help control blood pressure.
Outcomes Primary outcome was composite of cardiovascular and cerebrovascular events, including stroke, sud-
den death, MI, congestive heart failure, etc.
Notes Participants were recruited from 134 units located in northern, central, and southern Italy.
Risk of bias
Random sequence genera- Low risk Randomisation was made by BETA Trial Center, Genoa (Italy), using a sequen-
tion (selection bias) tially based criterion.

(selection bias)
Blinding (performance Unclear risk Method of blinding was not described.

All outcomes
All outcomes
porting bias)
Informed decisions.
STOP-Hypertension-2
Methods A prospective, randomised, open blinded endpoint trial with a follow-up of at least 4 years. No partic-
ipant was lost to follow-up, and no participant refused to continue in the study. Analysis was by inten-
tion-to-treat and of only the first occurrence of each event in question.
Participants Participants must have hypertension (BP ≥ 180 mmHg systolic, ≥ 105 mmHg diastolic, or both), and
were aged 70 to 84 years.
Interventions There were 3 groups, each of which was given a different class of drugs: conventional antihypertensive
drugs (N = 2213) (atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg, or fixed-ratio hydrochlorothiazide
25 mg plus amiloride 2.5 mg daily), ACE inhibitors (N = 2205) (enalapril 10 mg or lisinopril 10 mg daily),
or calcium antagonists (N = 2196) (felodipine 2.5 mg or isradipine 2.5 mg daily). Additional antihyper-
tensive drugs were allowed if necessary.
Outcomes The major outcomes were cardiovascular death, other cardiovascular event, and blood pressure
change.
Notes Study was conducted in 212 health centres in Sweden.
Risk of bias

(selection bias)

All outcomes
All outcomes
porting bias)
TOMHS
Methods A randomised, double-blind, placebo-controlled clinical trial. Participants were seen at least every 3
months for a median follow-up of 4.4 years. All analyses were by treatment allocation (intention-to-
treat).
Participants A total of 902 participants aged 45 to 69 years, with mild hypertension (diastolic BP was 90 to 99 mmHg
at both of the first 2 eligibility visits and averaged 90 to 99 mmHg over the 3 eligibility visits) were in-
cluded.
Informed decisions.
TOMHS (Continued)
Interventions Sustained nutritional-hygienic advice to all participants and increase physical activity. Participants
were randomly allocated to take (1) placebo (n = 234); (2) chlortalidone (15 mg/d, n = 136); (3) acebu-
tolol (400 mg/d, n = 132); (4) doxazosin mesylate (1 mg/d for 1 month, then 2 mg/d, n = 134); (5) am-
lodipine maleate (5 mg/d, n = 131); or (6) enalapril maleate (5 mg/d, n = 135). If BP was not well con-
trolled, drug dose was doubled, followed by use of additional drugs when necessary.
Outcomes Systolic and diastolic BP. Data on morbidity and mortality outcomes were not provided for the different
treatment arms.
Notes Study was conducted in 4 hypertension screening and treatment centres in the USA.
Risk of bias
Random sequence genera- Low risk A block randomisation scheme with stratification was used by clinical centre.

(selection bias)
Blinding (performance Low risk Active drugs and placebo administered to participants were prepared in iden-
bias and detection bias) tical capsule form.
All outcomes
All outcomes
porting bias)
VALUE
Methods A prospective, multinational, double-blind, randomised, active-controlled, parallel-group trial with a

mean follow-up time of 4.2 years. All endpoints and BP values were analysed using the intention-to-
treat approach.
Participants Enrolled participants were 50 years of age or older, with treated or untreated (mean sitting systolic BP
between 160 and 210 mmHg, and mean sitting diastolic BP of less than 115 mmHg) hypertension at
baseline and combinations of cardiovascular risk factors and cardiovascular disease. Additional antihy-
pertensive drugs excluding ARBs could be given to achieve BP goal.
Interventions Participants were randomised to either valsartan 80 mg (N = 7649) or amlodipine 5 mg (N = 7596).
Outcomes Time to first cardiac event, incidence of MI, heart failure and stroke, all-cause mortality, and new-onset
diabetes
Notes Study was carried out in 31 countries.
Risk of bias
Informed decisions.
VALUE (Continued)
Random sequence genera- Low risk Randomisation list was computer generated and prepared centrally by the
tion (selection bias) sponsor.

(selection bias)
Blinding (performance Low risk The study medication was provided in externally indistinguishable capsules.
All outcomes
Incomplete outcome data Unclear risk 68 participants in 9 centres were excluded after randomisation because of
(attrition bias) good clinical practice deficiencies, and were not included in intention-to-treat
All outcomes analyses, which could result in bias.
porting bias)
VART
Methods A multicentre, prospective, randomised, open-label, blinded endpoint trial. The mean follow-up period
was 3.4 years.
Participants A total of 1021 participants were enrolled. Age ≥ 30 years and recent diagnosis of hypertension (sys-
tolic ≥ 140 mmHg or diastolic BP ≥ 90 mmHg, with the patient in a sitting position at a clinic) or previ-
ous treatment with antihypertensive agents.
Interventions Participants were randomised to either valsartan 80 mg (N = 510) or amlodipine 5 mg (N = 511) per day.
The doses were increased to 160 or 10 mg per day, respectively, when necessary.
Outcomes The primary endpoint was a composite of all-cause death, sudden death, cerebrovascular death, car-
diac events, vascular events, and renal events.
The secondary endpoints were effects on left ventricular hypertrophy, cardiac sympathetic nerve activ-
ity, and renal function.
Notes The trial involved 92 medical facilities in Japan.
Risk of bias
Random sequence genera- Low risk The random assignment of participants, data entry, and data collection were
tion (selection bias) performed at the homepage originally produced for the trial, and the partici-
pants were assigned randomly to either the valsartan group or the amlodipine
group with the minimisation.

(selection bias)
Informed decisions.
VART (Continued)

All outcomes
Incomplete outcome data Low risk 15 participants withdrew consent and 11 were lost to follow-up in the valsar-
(attrition bias) tan group; 11 withdrew consent and 5 were lost to follow-up in amlodipine
All outcomes group. An intention-to-treat analysis was performed.
porting bias)
VHAS
Methods A multicentre, randomised, double-blind (for the first 6 months, open subsequently) parallel-group trial
lasting 2 years (prolonged to 4 years for the subgroup of participants evaluated by carotid ultrasonog-
raphy)
Participants Inclusion criteria were essential hypertension (systolic BP when seated ≥ 160 mmHg and diastolic BP
≥ 95 mmHg measured at the end of a placebo run-in period of 3 weeks), age of 40 to 65 years, of either
sex. A total of 1414 hypertensive participants were enrolled.
Interventions The study included a run-in period (3 weeks), a double-blind-treatment period (6 months, either 240
mg sustained release verapamil (n = 707) or 25 mg chlortalidone (n = 707) once a day), and an open-
treatment period (18 months); captopril was added to the treatment of non-responding participants;
free therapy of other drugs was permitted during follow-up when necessary.
Outcomes BP reduction, heart rate, clinical safety, cardiovascular events, death, and intima-media thickness
Notes Multicentre trial conducted in Italy
Risk of bias

(selection bias)
Blinding (performance Unclear risk Method of blinding was not described.

All outcomes
All outcomes
porting bias)
Informed decisions.
VHAS (Continued)
PROBE: Prospective, Randomised, Open-label, Blinded Endpoint
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Abascal 1998 Non-randomised trial
Abe 2013 Compared 2 kinds of CCBs, cilnidipine and amlodipine; no other classes of antihypertensive drugs
were studied
ACCOMPLISH Compared treatment with an angiotensin converting enzyme (ACE) inhibitor combined with am-
lodipine versus treatment with the same ACE inhibitor combined with a thiazide diuretic
Bakris 1996 Only 52 participants included in trial.
Bakris 1997 Only 34 participants included in trial.
BEAHIT Compared co-administration of a diuretic or calcium channel blocker (CCB) with an ACE inhibitor
Bhad 2011 Non-randomised trial
Calhoun 2013 Compared the antihypertensive efficacy and safety of once-daily triple therapy with amlodipine 10
mg, valsartan 320 mg, and hydrochlorothiazide 25 mg versus dual-therapy combinations of these
components
Follow-up lasted only 4 weeks and 8 weeks.
CASE-J Ex Another 3 years beyond the experimental period of the CASE-J trial. No useful data could be ex-
tracted from this extended study for the current review.
Chen 2013 A review that evaluated CCB versus placebo
Cicero 2012 162 participants were allocated to the combination of lercanidipine with -blockers, diuretics, ACE
inhibitors, and angiotensin receptor blockers (ARBs).
COLM Compared the cardiovascular effects of olmesartan, an ARB, combined with a CCB or a diuretic
DEMAND Compared manidipine/delapril combination with delapril or placebo
DHCCP Design was a combination of 2 case-control studies and 2 longitudinal studies.
Espinel 1992 Follow-up lasted only 8 weeks.
FACTS Only 96 participants were randomised to treatment in this study, which was less than the 100 ran-
domised participants specified in the protocol for the current review.
FEVER Compared the incidence of stroke and other cardiovascular events in hypertensive patients receiv-
ing a low-dose diuretic and low-dose calcium antagonist combination versus those receiving low-
dose diuretic monotherapy
GLANT Follow-up lasted for 12 months.
Informed decisions.
Gottdiener 1997 Study primarily evaluated the reduction of left ventricular mass; follow-up lasted only 1 year.
HOT Participants were randomly assigned to groups with different target diastolic blood pressure in-
stead of groups with different study drug.
Kereiakes 2012 Follow-up lasted only 12 weeks.
Kes 2003 Compared 2 kinds of CCBs, nifedipine and amlodipine; no other classes of antihypertensive drugs
were studied
Kim 2011 Only 32 participants included in trial.
Kojima 2013 Study concerned kidney-protective effects of azelnidipine versus a diuretic in combination with
olmesartan; follow-up lasted only 6 months.
Lauria 2012 380 hypertensive participants with albuminuria < 200 µg/min were randomised to at least 3-year
treatment with manidipine (10 mg/day) plus delapril (30 mg/day), delapril (30 mg/day), or placebo.
Leon 1993 Follow-up lasted only 22 weeks.
Maharaj 1992 Only 30 participants included in trial.
Mesci 2011 Only 80 participants were randomised to treatment in this study, which was less than the 100
randomised participants specified in the protocol for the current review; follow-up lasted only 6
months.
OSCAR Compared the efficacy of ARB uptitration to an ARB plus CCB combination
Pahor 1995 Prospective cohort study rather than a randomised controlled trial
Papademetriou 1997 Study primarily evaluated the reduction of left ventricular mass; follow-up lasted only 6 months.
PRESERVE Study primarily evaluated the reduction of left ventricular mass; follow-up lasted only 12 months.
Psaty 1995 Population-based case-control study instead of a randomised design
Radevski 1999 Only 96 participants included in trial.
Schneider 1991 Study aimed to evaluate the effect of therapy on hypertensive urgencies; follow-up was short.
STONE Non-randomised, placebo-controlled trial
Syst-China Non-randomised, placebo-controlled trial
Syst-Eur Placebo-controlled trial that did not compare CCBs with any other classes of drugs for hyperten-
sion
Van Leeuwen 1995 Study primarily evaluated the comparative effects of diltiazem and lisinopril on left ventricular
structure; follow-up lasted only 6 months.
Weir 1990 Follow-up lasted only 8 weeks.
Wen 2011 A total of 13,500 participants were randomly assigned to either low-dose amlodipine + telmisartan
group or amlodipine + diuretic group.
Informed decisions.
Zhang 2012 Follow-up lasted only 6 months.
DATA AND ANALYSES
Comparison 1. All-cause mortality
Outcome or subgroup title No. of studies No. of partici- Statistical method Effect size
pants
1.1 CCBs vs other classes of anti- 21 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
hypertensive agents
1.1.1 CCBs vs diuretics 5 35057 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.92, 1.04]
1.1.2 CCBs vs β-blockers 4 44825 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.88, 1.00]
1.1.3 CCBs vs diuretics or β- 3 31892 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.94, 1.12]
blockers
1.1.4 CCBs vs ACE inhibitors 7 27999 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.91, 1.03]
1.1.5 CCBs vs ARBs 6 25611 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.92, 1.08]
Informed decisions.
Analysis 1.1. Comparison 1: All-cause mortality, Outcome 1: CCBs vs other classes of antihypertensive agents


ALLHAT 1256 9048 2203 15255 85.1% 0.96 [0.90 , 1.03]
INSIGHT 153 3289 152 3286 7.9% 1.01 [0.81 , 1.25]
MIDAS 8 442 9 441 0.5% 0.89 [0.35 , 2.28]
SHELL 145 942 122 940 6.3% 1.19 [0.95 , 1.48]
VHAS 5 707 4 707 0.2% 1.25 [0.34 , 4.64]
Subtotal (95% CI) 14428 20629 100.0% 0.98 [0.92 , 1.04]

AASK 22 217 49 441 1.8% 0.91 [0.57 , 1.47]
ASCOT-BPLA 738 9639 820 9618 46.6% 0.90 [0.82 , 0.99]
ELSA 13 1177 17 1157 1.0% 0.75 [0.37 , 1.54]
INVEST 873 11267 893 11309 50.6% 0.98 [0.90 , 1.07]
Subtotal (95% CI) 22300 22525 100.0% 0.94 [0.88 , 1.00]

CONVINCE 337 8241 319 8361 34.8% 1.07 [0.92 , 1.25]
NORDIL 231 5410 228 5471 24.9% 1.02 [0.86 , 1.23]
Subtotal (95% CI) 15847 16045 100.0% 1.03 [0.94 , 1.12]

AASK 22 217 34 436 1.3% 1.30 [0.78 , 2.17]
ABCD 18 235 14 235 0.8% 1.29 [0.65 , 2.52]
ALLHAT 1256 9048 1314 9054 74.4% 0.96 [0.89 , 1.03]
FACET 5 191 4 189 0.2% 1.24 [0.34 , 4.54]
HOMED-BP 25 1171 17 1172 1.0% 1.47 [0.80 , 2.71]
J-MIC(B) 12 828 15 822 0.9% 0.79 [0.37 , 1.69]
Subtotal (95% CI) 13886 14113 100.0% 0.97 [0.91 , 1.03]
1.1.5 CCBs vs ARBs

CASE-J 86 2349 73 2354 7.0% 1.18 [0.87 , 1.60]
HOMED-BP 25 1171 16 1175 1.5% 1.57 [0.84 , 2.92]
IDNT 83 567 87 579 8.3% 0.97 [0.74 , 1.29]
NAGOYA 16 575 22 575 2.1% 0.73 [0.39 , 1.37]
VALUE 818 7596 841 7649 80.8% 0.98 [0.89 , 1.07]
VART 3 511 2 510 0.2% 1.50 [0.25 , 8.92]
Subtotal (95% CI) 12769 12842 100.0% 1.00 [0.92 , 1.08]
Informed decisions.
Analysis 1.1. (Continued)

0.5 0.7 1 1.5 2

Comparison 2. Myocardial infarction
pants
hypertensive agents
2.1.3 CCBs vs diuretics and β- 3 31892 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.93, 1.19]
blockers
2.2 Amlodipine vs ACE inhibitors 3 19135 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.91, 1.10]
Informed decisions.
Analysis 2.1. Comparison 2: Myocardial infarction, Outcome 1: CCBs vs other classes of antihypertensive agents


ALLHAT 798 9048 1362 15255 89.4% 0.99 [0.91 , 1.07]
INSIGHT 94 3289 84 3286 7.4% 1.12 [0.84 , 1.49]
MIDAS 8 442 7 441 0.6% 1.14 [0.42 , 3.12]
NICS-EH 2 215 2 214 0.2% 1.00 [0.14 , 7.00]
SHELL 28 942 27 940 2.4% 1.03 [0.61 , 1.74]
Subtotal (95% CI) 13936 20136 100.0% 1.00 [0.92 , 1.08]

AASK 5 217 19 441 2.5% 0.53 [0.20 , 1.41]
ASCOT-BPLA 429 9639 474 9618 94.1% 0.90 [0.79 , 1.03]
ELSA 18 1177 17 1157 3.4% 1.04 [0.54 , 2.01]
Subtotal (95% CI) 11033 11216 100.0% 0.90 [0.79 , 1.02]

CONVINCE 133 8241 166 8361 34.7% 0.81 [0.65 , 1.02]
NORDIL 183 5410 157 5471 32.9% 1.18 [0.96 , 1.45]
Subtotal (95% CI) 15847 16045 100.0% 1.05 [0.93 , 1.19]

AASK 5 217 18 436 1.2% 0.56 [0.21 , 1.48]
ABCD 27 235 9 235 0.9% 3.00 [1.44 , 6.24]
ALLHAT 798 9048 796 9054 79.5% 1.00 [0.91 , 1.10]
FACET 13 191 10 189 1.0% 1.29 [0.58 , 2.86]
HOMED-BP 12 1171 22 1172 2.2% 0.55 [0.27 , 1.10]
J-MIC(B) 16 828 13 822 1.3% 1.22 [0.59 , 2.52]
Subtotal (95% CI) 13886 14113 100.0% 1.05 [0.97 , 1.14]
2.1.5 CCBs vs ARBs

CASE-J 18 2349 17 2354 3.7% 1.06 [0.55 , 2.05]
HOMED-BP 12 1171 19 1175 4.2% 0.63 [0.31 , 1.30]
IDNT 27 567 44 579 9.5% 0.63 [0.39 , 1.00]
NAGOYA 3 575 7 575 1.5% 0.43 [0.11 , 1.65]
VALUE 313 7596 369 7649 80.6% 0.85 [0.74 , 0.99]
VART 1 511 2 510 0.4% 0.50 [0.05 , 5.49]
Subtotal (95% CI) 12769 12842 100.0% 0.82 [0.72 , 0.94]
Informed decisions.

0.2 0.5 1 2 5
Analysis 2.2. Comparison 2: Myocardial infarction, Outcome 2: Amlodipine vs ACE inhibitors
Amlodipine ACE inhibitors Risk Ratio Risk Ratio

AASK 5 217 18 436 1.5% 0.56 [0.21 , 1.48]

ALLHAT 798 9048 796 9054 97.3% 1.00 [0.91 , 1.10]
FACET 13 191 10 189 1.2% 1.29 [0.58 , 2.86]
Total (95% CI) 9456 9679 100.0% 1.00 [0.91 , 1.10]

Heterogeneity: Chi² = 1.75, df = 2 (P = 0.42); I² = 0% 0.01 0.1 1 10 100
Test for overall effect: Z = 0.00 (P = 1.00) Amlodipine ACE inhibitors
Test for subgroup differences: Not applicable
Comparison 3. Stroke
pants
hypertensive agents
blockers
3.2 Amlodipine vs ARBs 5 23265 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.74, 0.98]
Informed decisions.
Analysis 3.1. Comparison 3: Stroke, Outcome 1: CCBs vs other classes of antihypertensive agents


ALLHAT 377 9048 675 15255 80.3% 0.94 [0.83 , 1.07]
INSIGHT 67 3289 74 3286 11.8% 0.90 [0.65 , 1.25]
MIDAS 6 442 3 441 0.5% 2.00 [0.50 , 7.93]
NICS-EH 6 215 8 214 1.3% 0.75 [0.26 , 2.12]
SHELL 37 942 38 940 6.1% 0.97 [0.62 , 1.51]
Subtotal (95% CI) 13936 20136 100.0% 0.94 [0.84 , 1.05]

AASK 9 217 23 441 3.4% 0.80 [0.37 , 1.69]
ASCOT-BPLA 327 9639 422 9618 93.5% 0.77 [0.67 , 0.89]
ELSA 9 1177 14 1157 3.1% 0.63 [0.27 , 1.45]
Subtotal (95% CI) 11033 11216 100.0% 0.77 [0.67 , 0.88]

CONVINCE 133 8241 118 8361 21.4% 1.14 [0.89 , 1.46]
NORDIL 159 5410 196 5471 35.6% 0.82 [0.67 , 1.01]
Subtotal (95% CI) 15847 16045 100.0% 0.92 [0.81 , 1.03]

AASK 9 217 23 436 2.1% 0.79 [0.37 , 1.67]
ABCD 11 235 7 235 1.0% 1.57 [0.62 , 3.98]
ALLHAT 377 9048 457 9054 63.0% 0.83 [0.72 , 0.94]
FACET 10 191 4 189 0.6% 2.47 [0.79 , 7.75]
HOMED-BP 16 1171 11 1172 1.5% 1.46 [0.68 , 3.12]
J-MIC(B) 16 828 16 822 2.2% 0.99 [0.50 , 1.97]
Subtotal (95% CI) 13886 14113 100.0% 0.90 [0.81 , 0.99]
3.1.5 CCBs vs ARBs

CASE-J 47 2349 60 2354 13.7% 0.79 [0.54 , 1.15]
HOMED-BP 16 1171 9 1175 2.1% 1.78 [0.79 , 4.02]
IDNT 15 567 28 579 6.3% 0.55 [0.30 , 1.01]
NAGOYA 11 575 10 575 2.3% 1.10 [0.47 , 2.57]
VALUE 281 7596 322 7649 73.3% 0.88 [0.75 , 1.03]
VART 10 511 10 510 2.3% 1.00 [0.42 , 2.38]
Subtotal (95% CI) 12769 12842 100.0% 0.87 [0.76 , 1.00]
Informed decisions.

0.2 0.5 1 2 5
Analysis 3.2. Comparison 3: Stroke, Outcome 2: Amlodipine vs ARBs
Amlodipine ARBs Risk Ratio Risk Ratio

CASE-J 47 2349 60 2354 14.0% 0.79 [0.54 , 1.15]

IDNT 15 567 28 579 6.5% 0.55 [0.30 , 1.01]
NAGOYA 11 575 10 575 2.3% 1.10 [0.47 , 2.57]
VALUE 281 7596 322 7649 74.9% 0.88 [0.75 , 1.03]
VART 10 511 10 510 2.3% 1.00 [0.42 , 2.38]
Total (95% CI) 11598 11667 100.0% 0.85 [0.74 , 0.98]

Test for overall effect: Z = 2.29 (P = 0.02) Amlodipine ARBs
Comparison 4. Congestive heart failure
pants
hypertensive agents
blockers
Informed decisions.
Analysis 4.1. Comparison 4: Congestive heart failure, Outcome 1: CCBs vs other classes of antihypertensive agents


ALLHAT 706 9048 870 15255 94.9% 1.37 [1.24 , 1.51]
INSIGHT 26 3289 12 3286 1.8% 2.16 [1.09 , 4.28]
MIDAS 2 442 0 441 0.1% 4.99 [0.24 , 103.61]
NICS-EH 0 215 3 214 0.5% 0.14 [0.01 , 2.74]
SHELL 23 942 19 940 2.8% 1.21 [0.66 , 2.20]
Subtotal (95% CI) 13936 20136 100.0% 1.37 [1.25 , 1.51]

AASK 8 217 22 441 8.4% 0.74 [0.33 , 1.63]
ASCOT-BPLA 134 9639 159 9618 91.6% 0.84 [0.67 , 1.06]
Subtotal (95% CI) 9856 10059 100.0% 0.83 [0.67 , 1.04]

CONVINCE 126 8241 100 8361 30.2% 1.28 [0.98 , 1.66]
NORDIL 63 5410 53 5471 16.1% 1.20 [0.84 , 1.73]
Subtotal (95% CI) 15847 16045 100.0% 1.15 [0.99 , 1.33]

AASK 8 217 20 436 1.7% 0.80 [0.36 , 1.80]
ABCD 8 235 10 235 1.3% 0.80 [0.32 , 1.99]
ALLHAT 706 9048 612 9054 77.2% 1.15 [1.04 , 1.28]
J-MIC(B) 12 828 9 822 1.1% 1.32 [0.56 , 3.12]
Subtotal (95% CI) 12524 12752 100.0% 1.16 [1.06 , 1.28]
4.1.5 CCBs vs ARBs

CASE-J 16 2349 20 2354 4.6% 0.80 [0.42 , 1.54]
IDNT 93 567 60 579 13.6% 1.58 [1.17 , 2.14]
NAGOYA 15 575 3 575 0.7% 5.00 [1.46 , 17.18]
VALUE 400 7596 354 7649 80.5% 1.14 [0.99 , 1.31]
VART 1 511 3 510 0.7% 0.33 [0.03 , 3.19]
Subtotal (95% CI) 11598 11667 100.0% 1.20 [1.06 , 1.36]
0.2 0.5 1 2 5
Informed decisions.
Comparison 5. Cardiovascular mortality
pants
hypertensive agents
blockers
5.2 DHP vs β-blockers 3 22249 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.66, 0.90]
Informed decisions.
Analysis 5.1. Comparison 5: Cardiovascular mortality, Outcome 1: CCBs vs other classes of antihypertensive agents


ALLHAT 592 9048 992 15255 92.9% 1.01 [0.91 , 1.11]
INSIGHT 60 3289 52 3286 6.5% 1.15 [0.80 , 1.67]
NICS-EH 2 215 0 214 0.1% 4.98 [0.24 , 103.06]
VHAS 5 707 4 707 0.5% 1.25 [0.34 , 4.64]
Subtotal (95% CI) 13259 19462 100.0% 1.02 [0.93 , 1.12]

AASK 7 217 12 441 1.0% 1.19 [0.47 , 2.97]
ASCOT-BPLA 263 9639 342 9618 43.4% 0.77 [0.66 , 0.90]
ELSA 4 1177 8 1157 1.0% 0.49 [0.15 , 1.63]
INVEST 431 11267 431 11309 54.6% 1.00 [0.88 , 1.14]
Subtotal (95% CI) 22300 22525 100.0% 0.90 [0.81 , 0.99]

CONVINCE 152 8241 143 8361 29.8% 1.08 [0.86 , 1.35]
NORDIL 131 5410 115 5471 24.0% 1.15 [0.90 , 1.48]
Subtotal (95% CI) 15847 16045 100.0% 1.04 [0.92 , 1.18]

AASK 7 217 12 436 0.9% 1.17 [0.47 , 2.93]
ABCD 11 235 6 235 0.7% 1.83 [0.69 , 4.88]
ALLHAT 592 9048 609 9054 71.1% 0.97 [0.87 , 1.09]
HOMED-BP 4 1171 2 1172 0.2% 2.00 [0.37 , 10.91]
J-MIC(B) 6 828 6 822 0.7% 0.99 [0.32 , 3.07]
Subtotal (95% CI) 13695 13924 100.0% 0.98 [0.89 , 1.07]
5.1.5 CCBs vs ARBs

HOMED-BP 4 1171 2 1175 3.5% 2.01 [0.37 , 10.94]
IDNT 37 567 52 579 89.6% 0.73 [0.48 , 1.09]
NAGOYA 4 575 4 575 7.0% 1.00 [0.25 , 3.98]
Subtotal (95% CI) 2313 2329 100.0% 0.79 [0.54 , 1.15]
Total events: 45 58
0.2 0.5 1 2 5
Informed decisions.
Analysis 5.2. Comparison 5: Cardiovascular mortality, Outcome 2: DHP vs β-blockers
DHP β-blockers Risk Ratio Risk Ratio

AASK 7 217 12 441 2.2% 1.19 [0.47 , 2.97]

ASCOT-BPLA 263 9639 342 9618 95.5% 0.77 [0.66 , 0.90]
ELSA 4 1177 8 1157 2.3% 0.49 [0.15 , 1.63]
Total (95% CI) 11033 11216 100.0% 0.77 [0.66 , 0.90]

Test for overall effect: Z = 3.31 (P = 0.0009) DHP β-blockers
Comparison 6. Major cardiovascular events
pants
6.1 CCBs vs other classes of antihy- 14 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
pertensive agents
blockers
6.2 Sensitivity analysis: CCBs vs 4 24806 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.94, 1.02]
ACE inhibitors
Informed decisions.
Analysis 6.1. Comparison 6: Major cardiovascular events,

Outcome 1: CCBs vs other classes of antihypertensive agents


ALLHAT 2432 9048 3941 15255 91.2% 1.04 [1.00 , 1.09]
INSIGHT 200 3289 182 3286 5.7% 1.10 [0.90 , 1.33]
MIDAS 25 442 14 441 0.4% 1.78 [0.94 , 3.38]
SHELL 90 942 88 940 2.7% 1.02 [0.77 , 1.35]
Subtotal (95% CI) 13721 19922 100.0% 1.05 [1.00 , 1.09]

AASK 23 217 65 441 4.2% 0.72 [0.46 , 1.12]
ASCOT-BPLA 796 9639 937 9618 92.5% 0.85 [0.77 , 0.93]
ELSA 27 1177 33 1157 3.3% 0.80 [0.49 , 1.33]
Subtotal (95% CI) 11033 11216 100.0% 0.84 [0.77 , 0.92]

CONVINCE 793 8241 775 8361 62.7% 1.04 [0.94 , 1.14]
Subtotal (95% CI) 10437 10574 100.0% 1.02 [0.95 , 1.10]

AASK 23 217 61 436 1.3% 0.76 [0.48 , 1.19]
ALLHAT 2432 9048 2514 9054 82.5% 0.97 [0.92 , 1.02]
FACET 27 191 14 189 0.5% 1.91 [1.03 , 3.52]
J-MIC(B) 50 828 44 822 1.4% 1.13 [0.76 , 1.67]
Subtotal (95% CI) 12480 12706 100.0% 0.98 [0.94 , 1.02]
6.1.5 CCBs vs ARBs

CASE-J 96 2349 108 2354 72.0% 0.89 [0.68 , 1.17]
NAGOYA 38 575 27 575 18.0% 1.41 [0.87 , 2.27]
VART 12 511 15 510 10.0% 0.80 [0.38 , 1.69]
Subtotal (95% CI) 3435 3439 100.0% 0.97 [0.78 , 1.22]
0.7 0.85 1 1.2 1.5

Informed decisions.
Analysis 6.2. Comparison 6: Major cardiovascular events, Outcome 2: Sensitivity analysis: CCBs vs ACE inhibitors
CCBs ACE inhibitors Risk Ratio Risk Ratio

AASK 23 217 61 436 1.3% 0.76 [0.48 , 1.19]

ALLHAT 2432 9048 2514 9054 82.8% 0.97 [0.92 , 1.02]
J-MIC(B) 50 828 44 822 1.5% 1.13 [0.76 , 1.67]
Total (95% CI) 12289 12517 100.0% 0.98 [0.94 , 1.02]

Test for overall effect: Z = 1.04 (P = 0.30) CCBs ACE inhibitors
Comparison 7. Blood pressure reduction
pants
7.1 Systolic blood pressure 8 Mean Difference (IV, Fixed, 95% CI) Subtotals only
reduction
7.1.1 CCBs vs diuretics 3 24963 Mean Difference (IV, Fixed, 95% CI) 0.81 [0.56, 1.06]
7.1.2 CCBs vs β-blockers 3 23474 Mean Difference (IV, Fixed, 95% CI) 0.25 [-0.31, 0.81]
7.1.3 CCBs vs diuretics or β- 1 10881 Mean Difference (IV, Fixed, 95% CI) 3.00 [2.59, 3.41]
blockers
7.1.4 CCBs vs ACE inhibitors 4 19368 Mean Difference (IV, Fixed, 95% CI) -1.11 [-1.40, -0.82]
7.1.5 CCBs vs ARBs 1 15245 Mean Difference (IV, Fixed, 95% CI) -2.10 [-2.46, -1.74]
7.1.6 CCBs vs α1-antagonist 1 235 Mean Difference (IV, Fixed, 95% CI) -1.40 [-3.89, 1.09]
7.2 Diastolic blood pressure 8 Mean Difference (IV, Fixed, 95% CI) Subtotals only
reduction
7.2.1 CCBs vs diuretics 3 24963 Mean Difference (IV, Fixed, 95% CI) -0.68 [-0.84, -0.52]
7.2.2 CCBs vs β-blockers 3 23474 Mean Difference (IV, Fixed, 95% CI) 0.15 [-0.16, 0.45]
7.2.3 CCBs vs diuretics or β- 1 10881 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.07, 0.27]
blockers
7.2.4 CCBs vs ACE inhibitors 4 19368 Mean Difference (IV, Fixed, 95% CI) -0.63 [-0.81, -0.44]
7.2.5 CCBs vs ARBs 1 15245 Mean Difference (IV, Fixed, 95% CI) -1.70 [-1.91, -1.49]
7.2.6 CCBs vs α1-antagonists 1 235 Mean Difference (IV, Fixed, 95% CI) -1.20 [-2.39, -0.01]
7.3 Sensitivity analysis: CCBs 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
vs ACE inhibitors
Informed decisions.
pants
7.3.1 Systolic blood pressure 3 18988 Mean Difference (IV, Fixed, 95% CI) -1.00 [-1.29, -0.70]
reduction
7.3.2 Diastolic blood pressure 3 18988 Mean Difference (IV, Fixed, 95% CI) -0.62 [-0.81, -0.44]
reduction
Analysis 7.1. Comparison 7: Blood pressure reduction, Outcome 1: Systolic blood pressure reduction
CCBs Other agents Mean Difference Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI

ALLHAT -11.5 9.7 9048 -12.3 9.8 15255 97.1% 0.80 [0.55 , 1.05]
NICS-EH -24.9 9 215 -25.6 9.8 214 2.0% 0.70 [-1.08 , 2.48]
TOMHS -15.6 9.6 114 -17.7 10.8 117 0.9% 2.10 [-0.53 , 4.73]
Subtotal (95% CI) 9377 15586 100.0% 0.81 [0.56 , 1.06]

AASK -17 17 217 -15 15.67 441 4.3% -2.00 [-4.69 , 0.69]
INVEST -18.7 22.2 11267 -19 22.6 11309 91.2% 0.30 [-0.28 , 0.88]
TOMHS -15.6 9.6 114 -17 11.2 126 4.5% 1.40 [-1.23 , 4.03]
Subtotal (95% CI) 11598 11876 100.0% 0.25 [-0.31 , 0.81]

NORDIL -21.3 10.9 5410 -24.3 10.8 5471 100.0% 3.00 [2.59 , 3.41]
Subtotal (95% CI) 5410 5471 100.0% 3.00 [2.59 , 3.41]
Heterogeneity: Not applicable

AASK -17 17 217 -16 14.48 436 1.2% -1.00 [-3.64 , 1.64]
ALLHAT -11.5 9.7 9048 -10.5 10.8 9054 94.6% -1.00 [-1.30 , -0.70]
FACET -18 8.6 191 -13 8.6 189 2.8% -5.00 [-6.73 , -3.27]
TOMHS -15.6 9.6 114 -14.7 9.8 119 1.4% -0.90 [-3.39 , 1.59]
Subtotal (95% CI) 9570 9798 100.0% -1.11 [-1.40 , -0.82]
7.1.5 CCBs vs ARBs

VALUE -17.3 11.4 7596 -15.2 11.4 7649 100.0% -2.10 [-2.46 , -1.74]
Subtotal (95% CI) 7596 7649 100.0% -2.10 [-2.46 , -1.74]
7.1.6 CCBs vs α1-antagonist

TOMHS -15.6 9.6 114 -14.2 9.9 121 100.0% -1.40 [-3.89 , 1.09]
Subtotal (95% CI) 114 121 100.0% -1.40 [-3.89 , 1.09]
Test for subgroup differences: Chi² = 435.30, df = 5 (P < 0.00001), I² = 98.9% -4 -2 0 2 4

Favours CCB Favours other agents
Informed decisions.
Analysis 7.2. Comparison 7: Blood pressure reduction, Outcome 2: Diastolic blood pressure reduction
CCBs Other agents Mean Difference Mean Difference


ALLHAT -9.3 6.4 9048 -8.6 6.3 15255 96.4% -0.70 [-0.87 , -0.53]
NICS-EH -13.2 6.1 215 -13.5 6.2 214 1.9% 0.30 [-0.86 , 1.46]
TOMHS -12.9 4.3 114 -12.3 5.4 117 1.7% -0.60 [-1.86 , 0.66]
Subtotal (95% CI) 9377 15586 100.0% -0.68 [-0.84 , -0.52]

AASK -15 8.98 217 -14 8.68 441 4.5% -1.00 [-2.44 , 0.44]
INVEST -10 12.4 11267 -10.2 12.4 11309 89.6% 0.20 [-0.12 , 0.52]
TOMHS -12.9 4.3 114 -13.1 5.6 126 5.9% 0.20 [-1.06 , 1.46]
Subtotal (95% CI) 11598 11876 100.0% 0.15 [-0.16 , 0.45]

NORDIL -18.2 4.6 5410 -18.3 4.7 5471 100.0% 0.10 [-0.07 , 0.27]
Subtotal (95% CI) 5410 5471 100.0% 0.10 [-0.07 , 0.27]

AASK -15 8.98 217 -14 9.48 436 1.5% -1.00 [-2.49 , 0.49]
ALLHAT -9.3 6.4 9048 -8.7 6.6 9054 95.2% -0.60 [-0.79 , -0.41]
FACET -8 8.6 191 -7 8.6 189 1.1% -1.00 [-2.73 , 0.73]
TOMHS -12.9 4.3 114 -11.5 5.5 119 2.1% -1.40 [-2.66 , -0.14]
Subtotal (95% CI) 9570 9798 100.0% -0.63 [-0.81 , -0.44]
7.2.5 CCBs vs ARBs

VALUE -9.9 6.6 7596 -8.2 6.6 7649 100.0% -1.70 [-1.91 , -1.49]
Subtotal (95% CI) 7596 7649 100.0% -1.70 [-1.91 , -1.49]
7.2.6 CCBs vs α1-antagonists

TOMHS -12.9 4.3 114 -11.7 5 121 100.0% -1.20 [-2.39 , -0.01]
Subtotal (95% CI) 114 121 100.0% -1.20 [-2.39 , -0.01]
Test for subgroup differences: Chi² = 192.21, df = 5 (P < 0.00001), I² = 97.4% -4 -2 0 2 4

Informed decisions.
Analysis 7.3. Comparison 7: Blood pressure reduction, Outcome 3: Sensitivity analysis: CCBs vs ACE inhibitors
CCBs ACE inhibitors Mean Difference Mean Difference

7.3.1 Systolic blood pressure reduction

AASK -17 17 217 -16 14.48 436 1.3% -1.00 [-3.64 , 1.64]
ALLHAT -11.5 9.7 9048 -10.5 10.8 9054 97.3% -1.00 [-1.30 , -0.70]
TOMHS -15.6 9.6 114 -14.7 9.8 119 1.4% -0.90 [-3.39 , 1.59]
Subtotal (95% CI) 9379 9609 100.0% -1.00 [-1.29 , -0.70]
7.3.2 Diastolic blood pressure reduction

AASK -15 8.98 217 -14 9.48 436 1.6% -1.00 [-2.49 , 0.49]
ALLHAT -9.3 6.4 9048 -8.7 6.6 9054 96.3% -0.60 [-0.79 , -0.41]
TOMHS -12.9 4.3 114 -11.5 5.5 119 2.2% -1.40 [-2.66 , -0.14]
Subtotal (95% CI) 9379 9609 100.0% -0.62 [-0.81 , -0.44]
Test for subgroup differences: Chi² = 4.44, df = 1 (P = 0.04), I² = 77.5% -100 -50 0 50 100
CCBs ACE inhibitors
APPENDICES
Appendix 1. Search strategies

Database: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) <1946 to September
01, 2020>
Search Date: 2 September 2020
--------------------------------------------------------------------------------
1 exp calcium channel blockers/
2 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or
darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or
isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or
nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil
or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM).tw,kf. (63679)
3 (calcium adj2 (antagonist? or block$ or inhibit$)).tw,kf.
4 or/1-3
5 exp thiazides/
6 exp sodium chloride symporter inhibitors/
7 exp sodium potassium chloride symporter inhibitors/
8 ((loop or ceiling) adj diuretic?).tw,kf.
9 (amiloride or benzothiadiazine or bendroflumethiazide or bumetanide or chlorothiazide or cyclopenthiazide or furosemide or
hydrochlorothiazide or hydroflumethiazide or methyclothiazide or metolazone or polythiazide or trichlormethiazide or veratide or
thiazide?).tw,kf.
10 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or
metindamide).tw,kf.
11 or/5-10
12 exp angiotensin-converting enzyme inhibitors/
13 angiotensin converting enzyme inhibit$.tw,kf.
14 (ace adj2 inhibit$).tw,kf.
15 acei.tw,kf.
16 exp enalapril/
17 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril
or derapril or enalapril or enalaprilat or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or
indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril$ or perindopril$ or pivopril or quinapril$ or
ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril
$ or zofenopril$ or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril).tw,kf.
18 or/12-17
Informed decisions.
19 exp Angiotensin Receptor Antagonists/

20 (angiotensin adj3 receptor antagon$).tw,kf.
21 (angiotensin adj3 receptor block$).tw,kf.
22 (arb or arbs).tw,kf.
23 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan
or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or Atacand or Avapro or Benicar or Cozaar or Diovan
or Micardis or Teveten).tw,kf.
24 or/19-23
25 (methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa
or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin
or hydopa or methyldihydroxyphenylalanine or methyl dopa or mulfasin or presinol or presolisin or sedometil or sembrina or taquinil or
dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa).mp.
26 (reserpine or serpentina or rauwolfia or serpasil).mp.
27 (clonidine or adesipress or arkamin or caprysin or catapres$ or catasan or chlofazolin or chlophazolin or clinidine or clofelin$ or clofenil
or clomidine or clondine or clonistada or clonnirit or clophelin$ or dichlorophenylaminoimidazoline or dixarit or duraclon or gemiton or
haemiton or hemiton or imidazoline or isoglaucon or klofelin or klofenil or m-5041t or normopresan or paracefan or st-155 or st 155 or
tesno timelets).mp.
28 exp hydralazine/
29 (hydralazin$ or hydrallazin$ or hydralizine or hydrazinophtalazine or hydrazinophthalazine or hydrazinophtalizine or dralzine or
hydralacin or hydrolazine or hypophthalin or hypoftalin or hydrazinophthalazine or idralazina or 1-hydrazinophthalazine or apressin or
nepresol or apressoline or apresoline or apresolin or alphapress or alazine or idralazina or lopress or plethorit or praeparat).mp.
30 or/25-29
31 exp adrenergic beta-antagonists/
32 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol
or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol
or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol
or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol
or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or
iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or
mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or
nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol
or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or
talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol).tw,kf.
33 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw,kf.
34 or/31-33
35 hypertension/
36 essential hypertension/
37 (antihypertens$ or hypertens$).tw,kf.
38 exp blood pressure/
39 (blood pressur$ or bloodpressur$).mp.
40 or/35-39
41 randomized controlled trial.pt.
42 controlled clinical trial.pt.
43 randomized.ab.
44 placebo.ab.
45 dt.fs.
46 randomly.ab.
47 trial.ab.
48 groups.ab.
49 or/41-48
50 animals/ not (humans/ and animals/)
51 49 not 50
52 4 and (11 or 18 or 24 or 30 or 34) and 40 and 51
--------------------------------------------------------------------------------
Database: Cochrane Hypertension Specialised Register via Cochrane Register of Studies

--------------------------------------------------------------------------------
#1 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or
Informed decisions.
or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM) AND
INSEGMENT
#2 calcium NEAR2 (antagonist* OR block* OR inhibit*) AND INSEGMENT
#3 (#1 OR #2) AND INSEGMENT
#4 thiazide* AND INSEGMENT
#5 sodium chloride symporter inhibitor* AND INSEGMENT
#6 sodium potassium chloride symporter inhibitor* AND INSEGMENT
#7 ((loop OR ceiling) NEXT diuretic*) AND INSEGMENT
#8 (amiloride or benzothiadiazine or bendroflumethiazide or bumetanide or chlorothiazide or cyclopenthiazide or furosemide or
thiazide*) AND INSEGMENT
#9 (chlorthalidone OR chlortalidone OR phthalamudine OR chlorphthalidolone OR oxodoline OR thalitone OR hygroton OR indapamide
OR metindamide) AND INSEGMENT
#10 (#4 OR #5 OR #6 OR #7 OR #8 OR #9) AND INSEGMENT
#11 angiotensin converting enzyme inhibit* AND INSEGMENT
#12 (ace NEAR2 inhibit*) AND INSEGMENT
#13 (acei OR aceis) AND INSEGMENT
#14 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril
or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or
libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril* or perindopril* or pivopril or quinapril* or ramipril* or
rentiapril or saralasin or s nitrosocaptopril or spirapril* or temocapril* or teprotide or trandolapril* or utibapril* or zabicipril* or zofenopril*
or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril) AND INSEGMENT
#15 (#11 OR #12 OR #13 OR #14) AND INSEGMENT
#16 ((angiotensin NEAR3 receptor antagon*) OR (angiotensin NEAR3 receptor block*)) AND INSEGMENT
#17 (arb OR arbs) AND INSEGMENT
#18 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan
or Micardis or Teveten) AND INSEGMENT
#19 (#16 OR #17 OR #18) AND INSEGMENT
#20 (methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa or
methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin
dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa) AND INSEGMENT
#21 (reserpine OR serpentina OR rauwolfia OR serpasil) AND INSEGMENT
#22 (clonidine or adesipress or arkamin or caprysin or catapres* or catasan or chlofazolin or chlophazolin or clinidine or clofelin* or clofenil
or clomidine or clondine or clonistada or clonnirit or clophelin* or dichlorophenylaminoimidazoline or dixarit or duraclon or gemiton or
haemiton or hemiton or imidazoline or isoglaucon or klofelin or klofenil or "m-5041t" or normopresan or paracefan or "st-155" or "st 155"
or tesno timelets) AND INSEGMENT
#23 (hydralazin* or hydrallazin* or hydralizine or hydrazinophtalazine or hydrazinophthalazine or hydrazinophtalizine or dralzine or
hydralacin or hydrolazine or hypophthalin or hypoftalin or hydrazinophthalazine or idralazina or 1-hydrazinophthalazine or apressin
or nepresol or apressoline or apresoline or apresolin or alphapress or alazine or idralazina or lopress or plethorit or praeparat) AND
INSEGMENT
#24 (#20 OR #21 OR #22 OR #23) AND INSEGMENT
#25 (beta NEAR2 (adrenergic* OR antagonist* OR block* OR receptor*)) AND INSEGMENT
#26 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol
talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol) AND INSEGMENT
#28 (#3 AND (#10 OR #15 OR #19 OR #24 OR #27)) AND INSEGMENT
#29 RCT:DE AND INSEGMENT
#30 Review:ODE AND INSEGMENT
#32 #28 AND #31 AND INSEGMENT
Informed decisions.
--------------------------------------------------------------------------------
Database: Cochrane Central Register of Controlled Trials (Issue 8, 2020) via Cochrane Register of Studies
--------------------------------------------------------------------------------
#1 MESH DESCRIPTOR calcium channel blockers EXPLODE ALL AND CENTRAL:TARGET
CENTRAL:TARGET
#3 (calcium NEAR2 (antagonist* OR block* OR inhibit*)) AND CENTRAL:TARGET
#4 (#1 OR #2 OR #3) AND CENTRAL:TARGET
#5 MESH DESCRIPTOR thiazides EXPLODE ALL AND CENTRAL:TARGET
#6 MESH DESCRIPTOR sodium chloride symporter inhibitors EXPLODE ALL AND CENTRAL:TARGET
#7 MESH DESCRIPTOR sodium potassium chloride symporter inhibitors EXPLODE ALL AND CENTRAL:TARGET
#8 ((loop OR ceiling) NEXT diuretic*) AND CENTRAL:TARGET
thiazide*) AND CENTRAL:TARGET
OR metindamide) AND CENTRAL:TARGET
#11 (#5 OR #6 OR #7 OR #8 OR #9 OR #10) AND CENTRAL:TARGET
#12 MESH DESCRIPTOR Angiotensin-Converting Enzyme Inhibitors EXPLODE ALL AND CENTRAL:TARGET
#13 angiotensin converting enzyme inhibit* AND CENTRAL:TARGET
#14 (ace NEAR2 inhibit*) AND CENTRAL:TARGET
#15 acei AND CENTRAL:TARGET
#16 MESH DESCRIPTOR enalapril EXPLODE ALL AND CENTRAL:TARGET
or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril) AND CENTRAL:TARGET
#19 MESH DESCRIPTOR Angiotensin Receptor Antagonists EXPLODE ALL AND CENTRAL:TARGET
#20 ((angiotensin NEAR3 receptor antagon* OR angiotensin NEAR3 receptor block*)) AND CENTRAL:TARGET
#21 (arb OR arbs) AND CENTRAL:TARGET
or Micardis or Teveten) AND CENTRAL:TARGET
#23 (#19 OR #20 OR #21 OR #22) AND CENTRAL:TARGET
dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa) AND CENTRAL:TARGET
#25 (reserpine OR serpentina OR rauwolfia OR serpasil) AND CENTRAL:TARGET
or tesno timelets) AND CENTRAL:TARGET
#27 MESH DESCRIPTOR hydralazine EXPLODE ALL AND CENTRAL:TARGET
CENTRAL:TARGET
#29 (#24 OR #25 OR #26 OR #27 OR #28) AND CENTRAL:TARGET
#30 MESH DESCRIPTOR Adrenergic beta-Antagonists EXPLODE ALL AND CENTRAL:TARGET
#31 (beta NEAR2 (adrenergic* OR antagonist* OR block* OR receptor*)) AND CENTRAL:TARGET
Informed decisions.

talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol) AND CENTRAL:TARGET
#34 MESH DESCRIPTOR Hypertension AND CENTRAL:TARGET
#35 MESH DESCRIPTOR Essential Hypertension AND CENTRAL:TARGET
#36 (antihypertens* OR hypertens*) AND CENTRAL:TARGET
#37 MESH DESCRIPTOR Blood Pressure EXPLODE ALL AND CENTRAL:TARGET
#38 (blood pressur* OR bloodpressur*) AND CENTRAL:TARGET
#40 (#4 AND (#11 OR #18 OR #23 OR #29 OR #33) AND #39) AND CENTRAL:TARGET
--------------------------------------------------------------------------------
Database: Embase <1974 to 2020 September 01>

--------------------------------------------------------------------------------
1 exp calcium channel blocking agent/
2 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or
or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM).tw,kw.
(84571)
3 (calcium adj2 (antagonist? or block$ or inhibit$)).tw,kw.
4 or/1-3
5 exp thiazide diuretic agent/
6 exp loop diuretic agent/
7 ((loop or ceiling) adj diuretic?).tw,kw.
8 (amiloride or benzothiadiazine or bendroflumethiazide or bumetanide or chlorothiazide or cyclopenthiazide or furosemide or
thiazide?).tw,kw.
9 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or
metindamide).tw,kw.
10 or/5-9
11 exp dipeptidyl carboxypeptidase inhibitor/
12 angiotensin converting enzyme inhibit$.tw,kw.
13 (ace adj2 inhibit$).tw,kw.
14 acei.tw,kw.
15 enalapril/
16 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril
or derapril or enalapril or enalaprilat or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or
indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril$ or perindopril$ or pivopril or quinapril$ or
ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril$
or zofenopril$ or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril).tw,kw.
17 or/11-16
18 exp Angiotensin Receptor Antagonist/
19 (angiotensin adj3 receptor antagon$).tw,kw.
20 (angiotensin adj3 receptor block$).tw,kw.
21 (arb or arbs).tw,kw.
22 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan
or Micardis or Teveten).tw,kw.
23 or/18-22
24 (methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa
or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin
dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa).mp.
Informed decisions.
25 (reserpine or serpentina or rauwolfia or serpasil).mp.

26 (clonidine or adesipress or arkamin or caprysin or catapres$ or catasan or chlofazolin or chlophazolin or clinidine or clofelin$ or clofenil
or clomidine or clondine or clonistada or clonnirit or clophelin$ or dichlorophenylaminoimidazoline or dixarit or duraclon or gemiton or
haemiton or hemiton or imidazoline or isoglaucon or klofelin or klofenil or m-5041t or normopresan or paracefan or st-155 or st 155 or
tesno timelets).mp.
27 hydralazine/
28 (hydralazin$ or hydrallazin$ or hydralizine or hydrazinophtalazine or hydrazinophthalazine or hydrazinophtalizine or dralzine or
hydralacin or hydrolazine or hypophthalin or hypoftalin or hydrazinophthalazine or idralazina or 1-hydrazinophthalazine or apressin or
nepresol or apressoline or apresoline or apresolin or alphapress or alazine or idralazina or lopress or plethorit or praeparat).tw,kw.
29 or/24-28
30 exp beta adrenergic receptor blocking agent/
31 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol
talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol).tw,kw.
32 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw,kw.
33 or/30-32
34 exp hypertension/
35 (antihypertens$ or hypertens$).tw,kw.
36 exp blood pressure/
37 (blood pressur$ or bloodpressur$).mp.
38 or/34-37
39 randomized controlled trial/
40 crossover procedure/
41 double-blind procedure/
42 (randomi?ed or randomly).tw.
43 (crossover$ or cross-over$).tw.
44 placebo$.ab.
45 (doubl$ adj blind$).tw.
46 assign$.ab.
47 allocat$.ab.
48 or/39-47
49 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)
50 48 not 49
51 4 and (10 or 17 or 23 or 29 or 33) and 38 and 50
--------------------------------------------------------------------------------
Database: ClinicalTrials.gov
--------------------------------------------------------------------------------
Condition or disease: Hypertension
Other terms: randomized
Study type: Interventional Studies (Clinical Trials)
Intervention/treatment: Calcium Channel Blockers
First Posted: 02/18/2019 To 09/02/2020
--------------------------------------------------------------------------------
Database: WHO International Clinical Trials Registry Platform (ICTRP) via Cochrane Register of Studies
--------------------------------------------------------------------------------
#1 MESH DESCRIPTOR calcium channel blockers EXPLODE ALL AND CENTRAL:TARGET
Informed decisions.
CENTRAL:TARGET
#3 (calcium NEAR2 (antagonist* OR block* OR inhibit*)) AND CENTRAL:TARGET
#4 (#2 OR #3) AND CENTRAL:TARGET
#5 MESH DESCRIPTOR thiazides EXPLODE ALL AND CENTRAL:TARGET
#6 MESH DESCRIPTOR sodium chloride symporter inhibitors EXPLODE ALL AND CENTRAL:TARGET
#7 MESH DESCRIPTOR sodium potassium chloride symporter inhibitors EXPLODE ALL AND CENTRAL:TARGET
#8 ((loop OR ceiling) NEXT diuretic*) AND CENTRAL:TARGET
thiazide*) AND CENTRAL:TARGET
OR metindamide) AND CENTRAL:TARGET
#12 MESH DESCRIPTOR Angiotensin-Converting Enzyme Inhibitors EXPLODE ALL AND CENTRAL:TARGET
#13 angiotensin converting enzyme inhibit* AND CENTRAL:TARGET
#14 (ace NEAR2 inhibit*) AND CENTRAL:TARGET
#15 acei AND CENTRAL:TARGET
#16 MESH DESCRIPTOR enalapril EXPLODE ALL AND CENTRAL:TARGET
or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril) AND CENTRAL:TARGET
#19 MESH DESCRIPTOR Angiotensin Receptor Antagonists EXPLODE ALL AND CENTRAL:TARGET
#20 ((angiotensin NEAR3 receptor antagon* OR angiotensin NEAR3 receptor block*)) AND CENTRAL:TARGET
#21 (arb OR arbs) AND CENTRAL:TARGET
or Micardis or Teveten) AND CENTRAL:TARGET
#23 (#19 OR #20 OR #21 OR #22) AND CENTRAL:TARGET
dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa) AND CENTRAL:TARGET
#25 (reserpine OR serpentina OR rauwolfia OR serpasil) AND CENTRAL:TARGET
or tesno timelets) AND CENTRAL:TARGET
#27 MESH DESCRIPTOR hydralazine EXPLODE ALL AND CENTRAL:TARGET
CENTRAL:TARGET
#30 MESH DESCRIPTOR Adrenergic beta-Antagonists EXPLODE ALL AND CENTRAL:TARGET
#31 (beta NEAR2 (adrenergic* OR antagonist* OR block* OR receptor*)) AND CENTRAL:TARGET
talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol) AND CENTRAL:TARGET
#34 MESH DESCRIPTOR Hypertension AND CENTRAL:TARGET
#35 MESH DESCRIPTOR Essential Hypertension AND CENTRAL:TARGET
Informed decisions.
#36 (antihypertens* OR hypertens*) AND CENTRAL:TARGET

#38 (#4 AND (#11 OR #18 OR #23 OR #29 OR #33) AND #37) AND CENTRAL:TARGET
#39 (NCT0* or ACTRN* or ChiCTR* or DRKS* or EUCTR* or eudract* or IRCT* or ISRCTN* or JapicCTI* or JPRN* or NTR0* or NTR1* or NTR2*
or NTR3* or NTR4* or NTR5* or NTR6* or NTR7* or NTR8* or NTR9* or SRCTN* or UMIN0*):AU AND CENTRAL:TARGET
#40 http*:SO AND CENTRAL:TARGET
#41 (#39 OR #40) AND CENTRAL:TARGET
#42 #38 AND #41 AND CENTRAL:TARGET
Appendix 2. Search strategies from the 2010 review

Cochrane Central Register of Controlled Trials (CENTRAL)
--------------------------------------------------------------------------------
1. (calcium channel blockers or amlodipine or amrinone or bencyclane or bepridil or cinnarizine or conotoxins or diltiazem or felodipine
or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or magnesium sulfate or mibefradil or nicardipine or nifedipine or
nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or verapamil or omega-agatoxin iva or omega-conotoxin gvia or
omega-conotoxins).mp.
2. calcium adj2 (inhibit$ or agonist? or exogenous or blockader?).tw.
3. 1 or 2
4. hypertension/
5. hypertens$.tw.
6. (blood adj pressure).tw.
7. or/4-6
8. 3 and 7
--------------------------------------------------------------------------------
Ovid MEDLINE
--------------------------------------------------------------------------------
omega-conotoxins).mp.
3. 1 or 2
4. hypertension/
5. hypertens$.tw.
7. or/4-6
8. 3 and 7
9. randomized controlled trial.pt.
10. controlled clinical trial.pt.
11. randomized.ab.
12. placebo.ab.
13. drug therapy.fs.
14. randomly.ab.
15. trial.ab
16. groups.ab.
17. or/9-16
18. animals/ not (humans/ and animals/)
19. 17 not 18
20. 8 and 19
--------------------------------------------------------------------------------
Ovid Embase
--------------------------------------------------------------------------------
1. Randomized Controlled Trial/
2. Clinical Trial/
3. Multicenter Study/
4. Controlled Study/
5. Crossover Procedure/
6. Double Blind Procedure/
7. Single Blind Procedure/
8. exp Randomization/
Informed decisions.
9. Major Clinical Study/

10. Placebo/
11. Meta Analysis/
12. phase 2 clinical trial/ or phase 3 clinical trial/ or phase 4 clinical trial/
13. (clin$ adj25 trial$).tw.
14. ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).tw.
15. placebo$.tw.
16. random$.tw.
17. control$.tw.
18. (meta?analys$ or systematic review$).tw.
19. (cross?over or factorial or sham? or dummy).tw.
20. ABAB design$.tw.
21. or/1-20
22. human/
23. nonhuman/
24. 22 or 23
25. 21 not 24
26. 21 and 22
27. 25 or 26
28. hypertension/
29. hypertens$.tw.
31. or/28-30
32. exp calcium channel blockers/
omega-conotoxins).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug
manufacturer name]
35. or/32-34
36. 27 and 31 and 35
WHAT'S NEW
Date Event Description
7 January 2022 New citation required and conclusions We created 'Summary of findings' tables using GRADEpro soft-
have changed ware and assessed the overall quality of evidence for each out-
come based on GRADE criteria. Some main conclusions were
changed.
7 January 2022 New search has been performed We updated the literature searches and included five new stud-
ies in this updated review.
HISTORY
Protocol first published: Issue 2, 2002
Review first published: Issue 8, 2010
1 September 2020 New search has been performed The authors finished the first draft of the full review.
Informed decisions.
1 May 2009 New citation required and major Protocol re-published with new authors and amended methods.
changes
23 August 2006 New citation required and major Protocol withdrawn by authors.
changes
CONTRIBUTIONS OF AUTHORS
For the current version, Jiaying Zhu and Ning Chen selected and assessed studies. Jiaying Zhu drafted the review. Jiaying Zhu, Jie Zhou,
and Mengmeng Ma were responsible for the inclusion or exclusion of trials and data extraction. Jiaying Zhu, Muke Zhou, and Jian Guo
performed the analyses.
Cairong Zhu offered expert advice. Li He offered expert advice, reviewed the updated review, and was responsible for developing the review.
DECLARATIONS OF INTEREST
Jiaying Zhu, Ning Chen, Muke Zhou, Jian Guo, Cairong Zhu, Jie Zhou, Mengmeng Ma, and Li He declare that they have no competing
interests.
SOURCES OF SUPPORT
Internal sources
• West China Hospital, Sichuan University, China
This project was supported by National Key R＆D program of China (Nos. 2018YFC1311400 and 2018YFC1311401)
External sources
• no, Other
no
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

In the updated review, we added 'Summary of findings' tables and assessed the certainty of evidence for each outcome, which were not
mentioned in the protocol.
We amended the 'Types of participants' section in the Methods, adding "participants with diabetes mellitus with a BP of more than 135/85
mmHg".
NOTES
This protocol was first published in the Cochrane Library in Issue 2, 2002, by Onder G, Furberg CD, Moore A, Psaty BM, Pahor M. It was
subsequently withdrawn by the original authors in June 2006 because they were not able to continue working on it.
This review was updated in 2021.
INDEX TERMS
Medical Subject Headings (MeSH)

Angiotensin-Converting Enzyme Inhibitors [therapeutic use]; Antihypertensive Agents [adverse effects]; Calcium Channel Blockers
[adverse effects]; *Hypertension [drug therapy]; *Pharmaceutical Preparations
MeSH check words

Humans

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Cochrane

Calcium channel blockers versus other classes of drugs for

Zhu J, Chen N, Zhou M, Guo J, Zhu C, Zhou J, Ma M, He L

Zhu J, Chen N, Zhou M, Guo J, Zhu C, Zhou J, Ma M, He L.

Calcium channel blockers versus other classes of drugs for hypertension

Contact: Li He, [email protected].

Editorial group: Cochrane Hypertension Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Calcium channel blockers versus other classes of drugs for hypertension

What is the aim of this review?

We collected and analysed all relevant studies up to 01 September 2020.

Quality of the evidence

Summary of findings 1. CCBs versus diuretic for hypertension

Patient or population: patients with hypertension

Control CCBs versus diuretic

All-cause mortality Study population RR 0.98 35,057 ⊕⊕⊕⊝ NNH 83 (95%CI

Stroke Study population RR 0.94 34,072 ⊕⊕⊕⊝ NNT 236 (95%CI

Cochrane Database of Systematic Reviews

Summary of findings 2. CCBs versus β-blocker for hypertension

CCBs versus β-blocker for hypertension

Patient or population: patients with hypertension

Control CCBs versus β-blocker

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

1Only two studies described allocation concealment.

Cochrane Database of Systematic Reviews

CCBs versus ACE inhibitor for hypertension

Patient or population: patients with hypertension

Stroke Study population RR 0.90 27,999 ⊕⊕⊝⊝ NNT 185 (95%CI

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

CCBs versus ARB for hypertension

Patient or population: patients with hypertension

Control CCBs versus ARB

Stroke Study population RR 0.89 25,611 ⊕⊕⊕⊝ NNT 226 (95%CI

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

• US National Institutes of Health Ongoing Trials Measures of treatment effect

Figure 1. Study flow diagram.

Included studies BP ≥ 90 mmHg) separately, so data for hypertensive participants

Random sequence generation (selection bias)

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

Blinding (performance bias and detection bias): All outcomes

Selective reporting (reporting bias)

Allocation misconduct (ALLHAT; ASCOT-BPLA; CONVINCE; INSIGHT), which

CCBs Other agents Risk Ratio Risk Ratio

1.1.1 CCBs vs diuretics

1.1.2 CCBs vs β-blockers

1.1.3 CCBs vs diuretics or β-blockers

1.1.4 CCBs vs ACE inhibitors

1.1.5 CCBs vs ARBs

0.5 0.7 1 1.5 2

CCBs Other agents Risk Ratio Risk Ratio

3.1.1 CCBs vs diuretics

3.1.2 CCBs vs β-blockers

3.1.3 CCBs vs diuretics or β-blockers

3.1.4 CCBs vs ACE inhibitors